Phase 1/2 Dose Escalation and Efficacy Study of Anti-CD38 Monoclonal Antibody in Patients With Selected CD38+ Hematological Malignancies

• ClinicalTrials.gov Identifier: NCT01084252
• Recruitment Status: Completed
• First Posted: March 10, 2010
• Results First Posted: April 15, 2020
• Last Update Posted: October 6, 2023
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Study Description

Brief Summary:

Primary Objective:

Phase 1:

To determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) of SAR650984 (Isatuximab).

Phase 2 (stage 1):

To evaluate the activity of single-agent Isatuximab at different doses/schedules and to select dose and regimen to further evaluate the overall response rate (ORR) of Isatuximab as single agent or in combination with dexamethasone.

Phase 2 (stage 2):

To evaluate the activity in terms of overall response rate (ORR) of Isatuximab at the selected dose/schedule from stage1, as single agent (ISA arm) and in combination with dexamethasone (ISAdex arm).

Secondary Objectives:

Phase 1:

• To characterize the global safety profile including cumulative toxicities.
• To evaluate the pharmacokinetic (PK) profile of Isatuximab in the proposed dosing schedule(s).
• To assess the pharmacodynamics (PD), immune response, and preliminary disease response.

Phase 2 (stage 1): to evaluate the following objectives for Isatuximab as single agent:

• Safety
• Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival.

Phase 2 (stage 2): to evaluate the following objectives in each arm (ISA and ISAdex):

• Safety
• Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival.
• Participant-reported changes in health-related quality of life, symptoms of multiple myeloma and generic health status.
• Pharmacokinetic profile of Isatuximab.
• Immunogenicity of Isatuximab.
• Investigate the relationship between CD38 receptor density and CD38 receptor occupancy (Stage 1 only) on multiple myeloma cells and parameters of clinical response.

Condition or disease	Intervention/treatment	Phase
Hematological Malignancy	Drug: Isatuximab SAR650984; Drug: Dexamethasone	Phase 1; Phase 2

Detailed Description:

The Phase 1 study duration for an individual participant included a screening period for inclusion of up to 2 weeks, treatment with Isatuximab QW (every week) or Q2W (every 2 weeks) unless discontinued earlier due to safety or disease progression. Participants were followed for a minimum of 30 days following the last use of study drug or more than 30 days in case of unresolved toxicity, or up to initiation of another anticancer treatment.

The Phase 2 study duration for an individual participant included a screening period for inclusion of up to 3 weeks, then a treatment period and a follow up period. Treatment was continued until disease progression, unacceptable adverse reactions or other reasons for discontinuation. Participants were followed every 3 months following the last use of study drug until death or study cutoff, whichever came first.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 351 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/2 Dose Escalation Safety, Pharmacokinetic and Efficacy Study of Multiple Intravenous Administrations of a Humanized Monoclonal Antibody (SAR650984) Against CD38 in Patients With Selected CD38+ Hematological Malignancies
• Actual Study Start Date: June 10, 2010
• Actual Primary Completion Date: December 21, 2018
• Actual Study Completion Date: July 13, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1:Isatuximab <=1 mg/kg Q2W; Participants with CD38+ hematological malignancies (HM), received Isatuximab at any one of the dose less than or equal to (<=) 1 milligram per kilogram (mg/kg) (i.e. either 0.0001 mg/kg or 0.001 mg/kg or 0.01 mg/kg or 0.03 mg/kg or 0.1 mg/kg or 0.3 mg/kg or 1 mg/kg) as intravenous (IV) infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal by participant, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa
Experimental: Phase 1: Isatuximab 3mg/kg Q2W; Participants with CD38+ HM, received Isatuximab 3 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa
Experimental: Phase 1: Isatuximab 5 mg/kg Q2W; Participants with CD38+ HM, received Isatuximab 5 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa
Experimental: Phase1:Isatuximab (CD38+HM and Standard Risk Multiple Myeloma); Participants with CD38+ HM along with participants with standard risk multiple myeloma were included this arm and, received Isatuximab 10 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa
Experimental: Phase 1:Isatuximab (CD38 + HM and High Risk Multiple Myeloma); Participants with CD38+ HM along with participants with high risk multiple myeloma, received Isatuximab 10 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa
Experimental: Phase 1: Isatuximab 10 mg/kg QW; Participants with CD38+ HM, received Isatuximab 10 mg/kg, as IV infusion QW, i.e. on Day 1 and 8 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa
Experimental: Phase 1: Isatuximab 20 mg/kg Q2W; Participants with CD38+ HM, received Isatuximab 20 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa
Experimental: Phase 1: Isatuximab 20 mg/kg QW; Participants with CD38+ HM, received Isatuximab 20 mg/kg, as IV infusion QW, i.e. on Day 1 and 8 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa
Experimental: Phase 2 Stage 1a: Isatuximab 3 mg/kg Q2W; Participants with multiple Myeloma received Isatuximab 3 mg/kg, as IV infusion on Day 1 and Day 15 of each 28-day cycle until unacceptable adverse event (AE), disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 77 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa
Experimental: Phase 2 Stage 1a: Isatuximab 10 mg/kg Q2W; Participants with multiple Myeloma received Isatuximab 10 mg/kg, as IV infusion on Day 1 and Day 15 of each 28-day cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 77 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa
Experimental: Phase2 Stage1a:Isatuximab 10mg/kg Q2W; Then Q4W; Participants with multiple Myeloma received Isatuximab 10 mg/kg, as IV infusion Q2W, i.e. on Day 1 and Day 15 of Cycle 1 and 2 (each cycle 28 days), then every 4 week (Q4W), i.e. on Day 1 of each 28-days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 77 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa
Experimental: Phase 2 Stage 1b: Isatuximab 20mg/kg QW and Then Q2W; Participants with multiple Myeloma received Isatuximab 20 mg/kg, as IV infusion QW, i.e. on Day 1, 8, 15 and 22 of Cycle 1 and 2 (each cycle 28 days), then Q2W, i.e. on Day 1 and Day 15 of each 28-days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 53 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa
Experimental: Phase 2 Stage 2: Isatuximab Alone; Participants with relapsed or relapsed/refractory multiple myeloma (RRMM), received Isatuximab 20 mg/kg, as IV infusion on Day 1, 8, 15 and Day 22 of Cycle 1 (28 days) and then on Day 1 and 15 of each subsequent 28-day cycles until unacceptable AE, disease progression, poor compliance to the study protocol, study termination, lost to follow up or investigator's decision maximum exposure: 97 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa
Experimental: Phase 2 Stage 2: Isatuximab + Dexamethasone; Participants with relapsed or RRMM, received Isatuximab 20 mg/kg, as IV infusion on Day 1, 8, 15 and Day 22 of Cycle 1 (28 days) and then on Day 1 and 15 of each subsequent 28-day cycles along with dexamethasone: tablet or as IV infusion (40 mg/day for less than [<] 75 years of age; 20 mg/day [greater than or equal to [>=] for 75 years of age) on Days 1, 8, 15 and 22 of each 28 days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination, lost to follow up or investigator's decision (maximum exposure: 97 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa; Drug: Dexamethasone; Pharmaceutical form: solution for infusion Route of administration: intravenous; Drug: Dexamethasone; Pharmaceutical form: tablet Route of administration: oral

Outcome Measures

Primary Outcome Measures :

1. Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Day 1 of Cycle 1 up to Day 14 of Cycle 2 ]
   DLTs were assessed using the national cancer institute common terminology criteria for adverse events (NCI-CTCAE) version 4.03. DLTs were defined as any Grade 3 or higher non-hematological toxicity (with the exception of allergic reaction/hypersensitivity), Grade 4 neutropenia and/or Grade 4 thrombocytopenia lasting longer than 5 days, attributed to isatuximab. Any other toxicity that the Investigator and the Sponsor deemed to be dose-limiting, regardless of the grade, was also considered as DLT.
2. Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From Baseline up to 30 days after the last dose (maximum duration: 120 weeks ) ]
   Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened during the on-treatment period which was defined as the period from the time of first dose of study treatment until 30 days after the last dose of study treatment.
3. Phase 2 Stage 1: Percentage of Participants With Overall Response (OR) According to International Myeloma Working Group (IMWG) Uniform Response Criteria [ Time Frame: From the date of randomization until disease progression or death or data cut-off (maximum duration: 77 weeks ) ]
   OR defined as participants with stringent complete response (sCR) or complete response (CR) or very good partial response (VGPR) or partial response (PR) . Based on IMWG, CR: Negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and <=5% plasma cells in bone marrow; sCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; PR: >=50% reduction of serum M-Protein and reduction in urinary M-protein by >=90% or to <200 mg/24 hours; >=50% decrease in the difference between involved and uninvolved FLC levels in place of the M-protein criteria or a >=50% reduction in plasma cells in place of M-protein if present at baseline.
4. Phase 2 Stage 2: Percentage of Participants With Overall Response According to Updated IMWG Response Criteria [ Time Frame: From the date of randomization to date of death from any cause (maximum duration: 97 weeks) ]
   OR: participants with sCR or CR or VGPR or PR. As per updated IMWG, CR: Negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and <=5% plasma cells in bone marrow; normal FLC ratio of 0.26-1.65 in participants with only FLC disease; sCR: CR and normal FLC ratio and no clonal cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours, >90% decrease in the difference between involved and uninvolved FLC levels; PR: >=50% reduction of serum M-Protein and reduction in urinary M-protein by >=90% or to <200 mg/24 hours; >=50% decrease in the difference between involved and uninvolved FLC levels in place of M-protein criteria or >=50% reduction in plasma cells in place of M-protein if present at baseline.

Secondary Outcome Measures :

1. Pharmacokinetic (PK) Assessment: Phase 1: Plasma Concentration of Isatuximab Observed at the End of an Intravenous Infusion (Ceoi) [ Time Frame: Cycle 1 Day 1 and Cycle 3 Day 1: At the end of infusion ]
   Ceoi was defined as the plasma concentration of Isatuximab at end of infusion. Data for this outcome measure was planned to be collected and analyzed separately for dose 0.3 mg/kg, 1 mg/kg and not for 0.0001, 0.001, 0.01, 0.03 and 0.1 dose levels (reported under one arm, i.e. Phase 1: Isatuximab <=1mg/kg in participant flow). Analysis was performed on PK population: participants who gave informed consent, received at least one dose (even if incomplete) of isatuximab, had an assessable PK parameter.
2. PK Assessment: Phase 1: Maximum Observed Plasma Concentration (Cmax) of Isatuximab [ Time Frame: For Q2W:Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 3, 7, 24, 48 and 168 hr post-infusion; For QW: Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 4, 24, 48, 72 and 168 hr post-infusion ]
   Data for this outcome measure was planned to be collected and analyzed separately for dose 0.3 mg/kg, 1 mg/kg and not for 0.0001, 0.001, 0.01, 0.03 and 0.1 dose levels (reported under one arm, i.e. Phase 1: Isatuximab <=1mg/kg in participant flow). Analysis was performed on PK population.
3. PK Assessment: Phase 1: Time to Reach Maximum Plasma Concentration Observed (Tmax) of Isatuximab [ Time Frame: For Q2W:Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 3, 7, 24, 48 and 168 hr post-infusion; For QW: Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 4, 24, 48, 72 and 168 hr post-infusion ]
   Data for this outcome measure was planned to be collected and analyzed separately for dose 0.3 mg/kg, 1 mg/kg and not for 0.0001, 0.001, 0.01, 0.03 and 0.1 dose levels (reported under one arm, i.e. Phase 1: Isatuximab <=1mg/kg in participant flow). Analysis was performed on PK population.
4. PK Assessment: Phase 1: Plasma Concentration of Isatuximab at Week 1, 2 and 3 [ Time Frame: Week 1, 2 and 3 ]
   Data for this outcome measure was planned to be collected and analyzed only for dose 1 mg/kg and not for 0.0001, 0.001, 0.01, 0.03, 0.1 and 0.3 mg/kg dose levels (reported under one arm, i.e. Phase 1: Isatuximab <=1mg/kg in participant flow).
5. PK Assessment: Phase 1: Predicted Cumulative Area Under the Plasma Concentration Curve (AUC) of Isatuximab Over the First Week (0-168 Hours) (AUC1W) [ Time Frame: For Q2W:Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 3, 7, 24, 48 and 168 hr post-infusion; For QW: Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 4, 24, 48, 72 and 168 hr post-infusion ]
   Data for this outcome measure was planned to be collected and analyzed only for dose 1 mg/kg and not for 0.0001, 0.001, 0.01, 0.03, 0.1 and 0.3 mg/kg dose levels (reported under one arm, i.e. Phase 1: Isatuximab <=1mg/kg in participant flow).
6. PK Assessment: Phase 1: Predicted Cumulative Area Under the Plasma Concentration Curve (AUC) of Isatuximab Over the First 2 Weeks (0-336 Hours) (AUC2W) [ Time Frame: For Q2W:Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 3, 7, 24, 48 and 336 hr post-infusion; For QW: Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 4, 24, 48, 72 and 336 hr post-infusion ]
   Data for this outcome measure was planned to be collected and analyzed only for dose 1 mg/kg and not for 0.0001, 0.001, 0.01, 0.03, 0.1 and 0.3 mg/kg dose levels (reported under one arm, i.e. Phase 1: Isatuximab <=1mg/kg in participant flow).
7. Pharmacodynamic (PD) Assessment: Phase 1: Change From Baseline in Serum/Plasma Markers [ Time Frame: Cycle 1 Day 1 ]
   Serum/plasma markers included: tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1-β), interleukin 6 (IL-6) and interferon-gamma (IFN-Gamma). Due to change in planned analysis, data for high-sensitivity C-reactive protein (hs-CRP) and CD38 was not collected and analyzed.
8. Immunogenicity Assessment: Phase 1: Number of Participants With Treatment-Emergent And Treatment-Boosted Anti-drug Antibodies (ADA) Response [ Time Frame: Up to 120 weeks ]
   ADA response was categorized as: treatment induced and treatment boosted response. Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period (defined as the time from the first isatuximab administration until end of Phase 1) in participants without preexisting ADA (defined as: ADA that were present in samples drawn before treatment), including participants without pre-treatment (before treatment) samples. Treatment boosted ADA was defined as pre-existing ADA that increased at least 2 titer steps between pre-treatment (before treatment) and post-treatment.
9. Clinical Assessment: Phase 1: Percentage of Participants With Overall Response and Clinical Benefit: Assessed Using European Society for Blood and Marrow Transplantation (EBMT) Criteria [ Time Frame: From the date of randomization to the date of first documentation of progression or death (due to any cause) (maximum duration: 120 weeks) ]
   OR defined as participants with complete response (CR) or partial response (PR) as best overall response (BOR). Clinical benefit: participants with minimal response (MR) or better as BOR. BOR: best sequential response from start of treatment through the entire study excluding any time point following start of other treatment. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates, no increase in size or number of lytic bone lesions. PR: >=50% reduction of serum M-protein, reduction in 24 h urinary M-protein by >=90% or <200mg, >=50% reduction in size/number of soft tissue plasmacytomas, no increase in size or number of lytic bone lesions. MR: 25 to 49% reduction in serum M-protein, 50-89% reduction in 24h urine M-protein, 25-49% reduction in size of soft tissue plasmacytomas, no increase in size or number of lytic bone lesions.
10. Clinical Assessment: Phase 1: Duration of Response (DOR) [ Time Frame: From the date of first response to the date of first documentation of progression or death (due to any cause) (maximum duration: 120 weeks) ]
    DOR: time from first response (PR or better) to first documented tumor progression/death. Progression as per EBMT: >25% increase in serum monoclonal paraprotein level, which must also be an absolute increase of >= 5 g/l: confirmed by >=1 repeated investigation; >25% increase in 24h urinary light chain excretion, which must also be an absolute increase of >=200 mg/24 h:confirmed by >=1 repeated investigation; >25% increase in plasma cells in a bone marrow aspirate/on trephine biopsy, which must also be an absolute increase of >= 10%; definite increase in size of existing bone lesions/soft tissue plasmacytomas; development of new bone lesions/soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium >11·5 mg/dl or 2·8 mmol/l) not attributable to any other cause. PR: >=50% reduction of serum M-protein, reduction in 24h urinary M-protein by >=90% or <200mg, >=50% reduction in size/number of soft tissue plasmacytomas, no increase in size/number of lytic bone lesions.
11. Clinical Assessment: Phase 1: Time to First Response (TTR) [ Time Frame: From the date of first dose administration to the date of first response or death (due to any cause) (maximum duration: 120 weeks) ]
    TTR was defined as the time from first dose of isatuximab to first response (PR or better). PR: >=50% reduction of serum M-protein, reduction in 24 h urinary M-protein by >=90% or <200mg, >=50% reduction in size/number of soft tissue plasmacytomas, no increase in size or number of lytic bone lesions.
12. Clinical Assessment: Phase 1: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (Karnofsky Performance Status)-Shift From Baseline Value to Best Value During Treatment [ Time Frame: At baseline, during treatment (Day 1 up to 120 weeks) ]
    ECOG performance status was measured on a 4 point scale to assess participant's performance status. 0=Normal, fully functional; 1=Fatigue without significant decrease in daily activity; 2=Fatigue with significant impairment of daily activities or bed rest <50% of waking hours; 3=Bed rest/sitting >50% of waking hours; 4=Bedridden or unable to care for self, where lower score indicated good performance status. Number of participants with Baseline ECOG PS score and corresponding changes to the best values (categorized as: Baseline ECOG 1, During Treatment ECOG 0; Baseline ECOG 2, During Treatment ECOG 0; Baseline ECOG 2, During Treatment ECOG 1) are reported.
13. Clinical Assessment: Phase 1: Number of Participants With Eastern Cooperative Oncology Group Performance Status (Karnofsky Performance Status)-Shift From Baseline Value to Worst Value During Treatment [ Time Frame: At baseline, during treatment (up to 120 weeks) ]
    ECOG performance status was measured on a 4 point scale to assess participant's performance status. 0=Normal, fully functional; 1=Fatigue without significant decrease in daily activity; 2=Fatigue with significant impairment of daily activities or bed rest <50% of waking hours; 3=Bed rest/sitting>50% of waking hours; 4=Bedridden or unable to care for self, where higher score indicated worst performance status. Number of participants with Baseline ECOG PS score and corresponding changes to the worst values (categorized as: Baseline ECOG 0, During Treatment ECOG 1; Baseline ECOG 2, During Treatment ECOG 1; Baseline ECOG 0, During Treatment ECOG 2; Baseline ECOG 1, During Treatment ECOG 2; Baseline ECOG 0, During Treatment ECOG 3; Baseline ECOG 1, During Treatment ECOG 3; Baseline ECOG 2, During Treatment ECOG 3) are reported.
14. Phase 2 Stage 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From Baseline up to 30 days after the last dose (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) ]
    Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened during the on-treatment period which was defined as the period from the time of first dose of study treatment until 30 days after the last dose of study treatment.
15. Phase 2 Stage 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From Baseline up to 30 days after the last dose (maximum duration: 97 weeks) ]
    AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened during the on-treatment period which was defined as the period from the time of first dose of study treatment until 30 days after the last dose of study treatment.
16. Phase 2 Stage 1: Duration of Response [ Time Frame: From the date of first response until disease progression or death or data cut-off (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) ]
    DOR:Time from date of 1st IAC determined response (>= PR) that was subsequently confirmed, to date of first IAC determined PD/death, whichever happened earlier. updated IMWG criteria- PR:>=50% decrease in difference between involved and uninvolved FLC levels in place of M-protein criteria or a >=50% reduction in plasma cells in place of M-protein if baseline was ≥30%. If present at baseline a >=50% reduction in size of soft tissue plasmacytomas; PD: Increase of 25% from lowest response value in any of following: Serum M-protein >=0.5 g/dL absolute increase and/or urine M-protein >=200 mg/24 hours absolute increase and/or >10 mg/dL absolute increase in difference between involved and uninvolved FLC levels, >=10% bone marrow plasma cells (PCs), development of new bone lesions/soft tissue plasmacytomas or definite increase in size of existing bone lesions/soft tissue plasmacytomas, development of hypercalcemia (corrected serum calcium >11·5 mg/dl) attributed to PC proliferation disorder.
17. Phase 2 Stage 2: Duration of Response [ Time Frame: From the date of first response until disease progression or death or data cut-off (maximum duration: 97 weeks) ]
    DOR: Time from date of 1st IAC determined response (>= PR) that was subsequently confirmed, to date of 1st IAC determined PD or death, whichever happened earlier. As per updated IMWG criteria-PR: ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. ≥50% decrease in difference between involved and uninvolved FLC levels in place of M-protein criteria or ≥50% reduction in plasma cells in place of M-protein if baseline was ≥30%. If present at baseline ≥50% reduction in size of soft tissue plasmacytomas; PD: Increase of >25% from lowest response value in any one of following: Serum M-component (absolute increase must be >0.5 g/dL)4 and/or Urine M-component (absolute increase must be >200 mg/24 h) and/or >10 mg/dL absolute increase in difference between involved and uninvolved FLC levels, >=10% bone marrow plasma cell, development of hypercalcemia (corrected serum calcium >11.5 mg/dL) attributed solely to plasma cell proliferative disorder.
18. Phase 2 Stage 1: Percentage of Participants With Clinical Benefit [ Time Frame: From Baseline up to 30 days after the last dose (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) ]
    Clinical benefit: participants with sCR, CR, VGPR, PR or MR as per IMWG criteria, determined by IAC. CR: negative immunofixation on serum & urine, disappearance of any soft tissue plasmacytomas,<5% PCs in bone marrow aspirates. sCR: CR + normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. VGPR: serum & urine M-component detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-component plus urine M-component level <100mg/24hours; PR: ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours, ≥50% decrease in the difference between involved and uninvolved FLC levels in place of the M-protein criteria or a ≥50% reduction in plasma cells in place of M-protein if baseline was ≥30%. If present at baseline, ≥50% size reduction in soft tissue plasmacytomas. MR:>=25 but <49% reduction in serum M-protein, reduction in 24h urine M-protein by 50-89%, 25-49% size reduction in soft tissue plasmacytomas.
19. Phase 2 Stage 2: Percentage of Participants With Clinical Benefit [ Time Frame: From the date of randomization to the date of first documentation of progression or death (maximum duration: 97 weeks ) ]
    Clinical benefit:participants with sCR, CR, VGPR, PR or MR, per IMWG criteria, determined by IAC. CR:negative immunofixation on serum & urine, disappearance of any soft tissue plasmacytomas,<5% plasma cells in bone marrow aspirates,normal FLC ratio(0.26-1.65) in participants with only FLC disease.sCR:CR+normal FLC ratio, absence of clonal cells in bone marrow biopsy.VGPR:serum & urine M-component detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-component plus urine M-component level <100mg/24h/,>=90% decrease in difference between involved and uninvolved FLC levels; PR:>=50% reduction of serum M-protein, reduction in 24h urinary M-protein by >=90%/<200mg/24h,>50% decrease in difference between involved and uninvolved FLC in place of M-protein criteria, >=50% reduction in size/number of soft tissue plasmacytomas. MR:>=25 but <49% reduction in serum M-protein,reduction in 24h urine M-protein by 50-89%, 25-49% reduction in size of soft tissue plasmacytomas
20. Phase 2 Stage 1: Progression Free Survival (PFS) [ Time Frame: From the date of the first dose administration until progression or death, whichever occurred first (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) ]
    PFS was defined as the time interval from the date of first isatuximab administration to the date of the first IAC-confirmed disease progression (PD) or date of death due to any cause, whichever came first. As per IMWG criteria, PD: Increase of > 25% from lowest response value in any one or more of the following: Serum M-component and/or (the absolute increase must be > 0.5 g/dL), Urine M-component and/or (the absolute increase must be > 200 mg/24 h), > 10mg/dL decrease in the difference between involved and uninvolved FLC levels in place of the M-protein criteria, >10% absolute percentage of bone marrow plasma cell, definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas, development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that attributed solely to the plasma cell proliferative disorder. Analysis was performed by Kaplan-Meier method.
21. Phase 2 Stage 2: Progression Free Survival [ Time Frame: From the date of the first dose administration until progression or death, whichever occurred first (maximum duration: 97 weeks) ]
    PFS was defined as the time interval from the date of first isatuximab administration to the date of the first IAC-confirmed disease progression or the date of death due to any cause, whichever came first. As per IMWG criteria, PD: Increase of >25% from lowest response value in any one of the following: Serum M-component (the absolute increase must be >0.5 g/dL)4 and/or Urine M-component (the absolute increase must be >200 mg/24 h) and/or >10 mg/dL decrease in the difference between involved and uninvolved FLC levels in place of the M-protein criteria, ≥10% bone marrow plasma cell, development of hypercalcemia (corrected serum calcium >11.5 mg/dL) attributed solely to the plasma cell proliferative disorder. Analysis was performed by Kaplan-Meier method.
22. Phase 2 Stage 1: Overall Survival (OS) [ Time Frame: From the date of randomization to date of death from any cause (maximum duration 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) ]
    OS was defined as the time interval from the date of first Isatuximab administration to death from any cause. Analysis was performed by Kaplan-Meier method.
23. Phase 2 Stage 2: Overall Survival [ Time Frame: From the date of randomization to date of death from any cause (maximum duration: 97 weeks) ]
    OS was defined as the time interval from the date of first Isatuximab administration to death from any cause. Analysis was performed by Kaplan-Meier method.
24. Phase 2 Stage 1: Change From Baseline in Health Related Quality of Life (HRQL) European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Scores: Global Health Status [ Time Frame: Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10 and End of Treatment (EOT: anytime up to 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) ]
    EORTC-QLQ-C30 is a cancer-specific instrument with 30 questions for evaluation of new chemotherapy and provides an assessment of participant reported outcome dimensions. First 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical, role, emotional, cognitive, social), 3 symptom scales (fatigue, nausea/vomiting, pain) & other single items. For each item, high score = high level of symptomatology/problem. Last 2 questions represented participant's assessment of overall health & quality of life, coded on 7-point scale (1=very poor to 7=excellent). EORTC QLQ-C30 observed values and change from baseline for global health status (scoring of questions 29 & 30) and 5 functional scales, 3 symptom scales and other single items (scoring of questions 1 to 28). Answers were converted into grading scale, with values between 0 and 100. A high score represented a favorable outcome with a best quality of life for participant.
25. Phase 2 Stage 1: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Multiple Myeloma Specific Module With 20 Items (EORTC QLQ-MY20) Scores: Disease Symptom Subscale Score [ Time Frame: Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10 and EOT (anytime up to 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) ]
    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with MM. It has 4 subscales: body image, future perspective), and 2 symptoms scales (disease symptoms and side-effects of treatment). Disease symptoms subscale used 4-point scale ranged from 1= 'Not at All' to 4= 'Very Much'. Scores were averaged, and transformed to 0 -100 scale, where higher scores = more symptoms and lower health-related quality of life (HRQL) and lower score = less symptoms and more HRQL.
26. Phase 2 Stage 1: Change From Baseline in Euro Quality of Life 5 Dimension (EQ-5D) Generic Health Status - Visual Analogue Scale Scores [ Time Frame: Baseline, Day 1 of Cycles 4, 7, 10, 13, 16, 19, and EOT (anytime up to 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) ]
    EQ-5D was a standardized HRQL questionnaire consisting of EQ-5D descriptive system and Visual Analogue Scale (VAS). EQ-5D VAS was used to record a participant's rating for his/her current health-related quality of life state and captured on a vertical VAS (0-100), where 0 = worst imaginable health state and 100 = best imaginable health state.
27. Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 1 Week Interval [ Time Frame: Pre-dose, at the end of infusion, 1 hour and 168 hours post dose on Day 1 of Cycle 1 ]
28. Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 2 Weeks Interval [ Time Frame: Cycle 1, Day 1: pre-dose, at the end of infusion, 168 and 336 hours post-infusion ]
29. Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 4 Weeks Interval [ Time Frame: Cycle 1, Day 1: pre-dose, at the end of infusion, 168, 336, and 672 hours post-infusion ]
30. Pharmacokinetic Assessment: Phase 2 Stage 2: Plasma Concentration of Isatuximab Before Treatment Administration (Ctrough) [ Time Frame: At Day 1, 8, and 22 ]
31. Pharmacokinetic Assessment: Phase 2 Stage 2: Accumulation Ratio of Isatuximab Based on Ctrough [ Time Frame: Cycle 2, Day 1; Cycle 1, Day 8; Cycle 4, Day 1 ]
    Ctrough is the plasma concentration observed before treatment administration. For 1st category, the accumulation ratio was calculated by dividing Ctrough value of Cycle 2 Day 1 by Cycle 1 Day 8 and for second category, accumulation ratio was calculated by dividing Ctrough value of Cycle 4 Day 1 by Cycle 1 Day 8.
32. Immunogenicity Assessment: Phase 2 Stage 2: Number of Participants With Anti-drug Antibodies to Isatuximab [ Time Frame: Up to 97 weeks ]
    ADA response was categorized as: treatment induced and treatment boosted response. Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period (defined as the time from the first isatuximab administration until end of Phase 2 Stage 2) in participants without preexisting ADA (defined as: ADA that were present in samples drawn before treatment), including participants without pre-treatment (before treatment) samples. Treatment boosted ADA was defined as pre-existing ADA that increased at least 2 titer steps between pre-treatment (before treatment) and post-treatment.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

Phase 1:

• For dose escalation cohorts, participants with confirmed selected CD38+ hematological malignancies as specified below who had progressed on after standard therapy or for whom there was no effective standard therapy (refractory/relapsed participants). B-cell Non-Hodgkin-lymphoma/leukemia (NHL) participants with at least 1 measurable lesion. Multiple myeloma (MM) participants with measurable M-protein serum and/or 24-hour urine. Acute myeloid leukemia (AML) participants, all types except M3 based on French-American-British (FAB) classification. Acute Lymphoblastic Leukemia (B-cell ALL) participants. Chronic lymphocytic leukemia (CLL) participants.
• For expansion cohorts, participants with relapsed/refractory MM with measurable M-protein (serum M-protein of >0.5 g/dL and/or urine M-protein of >200 mg (24-hr urine)) or elevated serum free light chains (FLC) >10 mg/dL with abnormal FLC ratio) who had progressed on or after standard therapy that included an Immunomodulatory drug (IMiD) and a proteasome inhibitor and who met the protocol defined criteria for standard risk or high risk.

Phase 2:

• Participants had a known diagnosis of multiple myeloma with evidence of measurable disease, and have evidence of disease progression based on International Myeloma Working Group (IMWG) criteria: Serum M-protein ≥1 g/dL, or urine M-protein >=200 mg/24 hours or in the absence of measurable m-protein, serum FLC >=10 mg/dL, and abnormal serum immunoglobulin kappa lambda FLC ratio (<0.26 or >1.65).
• Participants who received at least three prior lines of therapy for MM and had treatment with an IMiD (for >=2 cycles or >=2 months of treatment) and a proteasome inhibitor (PI) (for >=2 cycles or >=2 months of treatment) OR participants whose disease was double refractory to an IMiD and a PI. For participants who had received more than 1 type of IMiD and PI, their disease must be refractory to the most recent one.
• Participants who had achieved a minimal response or better to at least one prior line of therapy.
• Participants who had received an alkylating agent (>=2 cycles or >=2 months) either alone or in combination with other MM treatments.
• Stage 2 only: Participants who had evidence of disease progression on or after the most recent prior regimen based on IMWG criteria.

Exclusion criteria:

Phase 1:

• Karnofsky performance status <60
• Poor bone marrow reserve
• Poor organ function
• Known intolerance to infused protein products, sucrose, histidine, polysorbate 80 or known hypersensitivity to any of the components of the study therapy that was not amenable to pre-medication with steroids and H2 blockers
• Any serious active disease (including clinically significant infection that was chronic, recurrent, or active) or co-morbid condition, which, in the opinion of the investigator, interfered with the safety, the compliance with the study or with the interpretation of the results
• Any severe underlying medical conditions including presence of laboratory abnormalities, which could impair the ability to participate in the study or the interpretation of its results

Phase 2:

• Participants with multiple myeloma immunoglobulin M (IgM) subtype
• Previous treatment with any anti-CD38 therapy
• Participants with concurrent plasma cell leukemia
• Participants with known or suspected amyloidosis
• Karnofsky performance status <60 (stage 1)/Eastern Cooperative Oncology Group (ECOG) Performance status >2 (stage 2).
• Poor bone marrow reserve
• Poor organ function
• Known intolerance to infused protein products, sucrose, histidine, polysorbate 80 or known hypersensitivity to any of the components of the study therapy that was not amenable to pre-medication with steroids and H2 blockers
• Any serious active disease (including clinically significant infection that was chronic, recurrent, or active) or co-morbid condition, which, in the opinion of the investigator, interfered with the safety, the compliance with the study or with the interpretation of the results
• Any severe underlying medical conditions including presence of laboratory abnormalities, which impaired the ability to participate in the study or the interpretation of its results

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Contacts and Locations

Locations

United States, Arizona

Investigational Site Number 840003

Scottsdale, Arizona, United States, 85054

United States, California

Investigational Site Number 840005

San Francisco, California, United States, 94117

United States, Georgia

Investigational Site Number 840009

Atlanta, Georgia, United States, 30322

United States, Illinois

Investigational Site Number 840010

Chicago, Illinois, United States, 60637

United States, Michigan

Investigational Site Number 840022

Ann Arbor, Michigan, United States, 48109-0759

Investigational Site Number 840027

Detroit, Michigan, United States, 48201

United States, Minnesota

Investigational Site Number 840018

Rochester, Minnesota, United States, 55905

United States, Missouri

Investigational Site Number 840013

Saint Louis, Missouri, United States, 63110

United States, New Jersey

Investigational Site Number 840011

Hackensack, New Jersey, United States, 07601

United States, New York

Investigational Site Number 840014

New York, New York, United States, 10021

United States, North Carolina

Investigational Site Number 840016

Durham, North Carolina, United States, 27707

United States, Ohio

Investigational Site Number 840004

Cincinnati, Ohio, United States, 45267-0542

United States, Tennessee

Investigational Site Number 840001

Nashville, Tennessee, United States, 37232

United States, Utah

Investigational Site Number 840002

Salt Lake City, Utah, United States, 84112-5550

United States, Washington

Investigational Site Number 840012

Seattle, Washington, United States, 98109

United States, Wisconsin

Investigational Site Number 840017

Milwaukee, Wisconsin, United States, 53226

Argentina

Investigational Site Number 032002

Caba, Argentina, C1181ACH

Investigational Site Number 032003

Capital Federal, Argentina, C1425ASS

Investigational Site Number 032001

Ciudad De Buenos Aires, Argentina, C1426ANZ

Belgium

Investigational Site Number 056001

Antwerpen, Belgium, 2060

Brazil

Investigational Site Number 076001

Barretos, Brazil, 14784-400

Investigational Site Number 076003

Porto Alegre, Brazil, 90470-340

Investigational Site Number 076004

Rio De Janeiro, Brazil, 22793-080

Investigational Site Number 076002

Sao Paulo, Brazil, 04537-081

Chile

Investigational Site Number 152001

Temuco, Chile, 4810469

Finland

Investigational Site Number 246001

Helsinki, Finland, 00029

Investigational Site Number 246002

Turku, Finland, 20521

France

Investigational Site Number 250003

Nantes Cedex 01, France, 44093

Investigational Site Number 250004

Pierre Benite, France, 69310

Investigational Site Number 250001

Toulouse Cedex 9, France, 31059

Greece

Investigational Site Number 300001

Athens, Greece, 11528

Israel

Investigational Site Number 376004

Jerusalem, Israel, 91120

Investigational Site Number 376002

Tel Hashomer, Israel, 52621

Italy

Investigational Site Number 380001

Bologna, Italy, 40138

Investigational Site Number 380002

Torino, Italy, 10126

Mexico

Investigational Site Number 484001

Monterrey, Mexico, 64460

Investigational Site Number 484003

San Luis Potosi, Mexico, 78419

Peru

Investigational Site Number 604001

Arequipa, Peru

Investigational Site Number 604002

Lima, Peru, LIMA 34

Russian Federation

Investigational Site Number 643002

Moscow, Russian Federation, 125284

Investigational Site Number 643003

Novosibirsk, Russian Federation, 630087

Investigational Site Number 643001

Petrozavodsk, Russian Federation, 185019

Investigational Site Number 643004

Saint-Petersburg, Russian Federation, 194291

Spain

Investigational Site Number 724007

Badalona, Spain, 08916

Investigational Site Number 724005

Barcelona, Spain, 08036

Investigational Site Number 724004

Madrid, Spain, 28041

Investigational Site Number 724002

Pamplona, Spain, 31008

Investigational Site Number 724001

Salamanca, Spain, 37007

Investigational Site Number 724008

Sevilla, Spain, 41013

Investigational Site Number 724006

Valencia, Spain, 46017

Turkey

Investigational Site Number 792002

Ankara, Turkey, 06200

Investigational Site Number 792005

Ankara, Turkey, 06500

Investigational Site Number 792001

İstanbul, Turkey

Investigational Site Number 792004

Samsun, Turkey, 55139

Ukraine

Investigational Site Number 804001

Kyiv, Ukraine, 04112

Investigational Site Number 804004

Vinnitsya, Ukraine, 21018

Investigational Site Number 804002

Zaporizhzhya, Ukraine, 69600

United Kingdom

Investigational Site Number 826001

Nottingham, United Kingdom, NG5 1PB

Investigational Site Number 826002

Southampton, United Kingdom, SO16 6YD

Sponsors and Collaborators

Sanofi

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

  Study Documents (Full-Text)

Documents provided by Sanofi:

Study Protocol  [PDF] June 11, 2019

Statistical Analysis Plan  [PDF] August 6, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Dimopoulos M, Bringhen S, Anttila P, Capra M, Cavo M, Cole C, Gasparetto C, Hungria V, Jenner M, Vorobyev V, Ruiz EY, Yin JY, Saleem R, Hellet M, Mace S, Paiva B, Vij R. Isatuximab as monotherapy and combined with dexamethasone in patients with relapsed/refractory multiple myeloma. Blood. 2021 Mar 4;137(9):1154-1165. doi: 10.1182/blood.2020008209.

Mikhael J, Richter J, Vij R, Cole C, Zonder J, Kaufman JL, Bensinger W, Dimopoulos M, Lendvai N, Hari P, Ocio EM, Gasparetto C, Kumar S, Oprea C, Chiron M, Brillac C, Charpentier E, San-Miguel J, Martin T. A dose-finding Phase 2 study of single agent isatuximab (anti-CD38 mAb) in relapsed/refractory multiple myeloma. Leukemia. 2020 Dec;34(12):3298-3309. doi: 10.1038/s41375-020-0857-2. Epub 2020 May 14.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01084252
• Other Study ID Numbers: TED10893; U1111-1116-5472 ( Other Identifier: UTN )
• First Posted: March 10, 2010
• Results First Posted: April 15, 2020
• Last Update Posted: October 6, 2023
• Last Verified: October 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Keywords provided by Sanofi:

Anti-CD38 monoclonal antibody

Additional relevant MeSH terms:

Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Hematologic Diseases; Dexamethasone; Dexamethasone acetate; BB 1101; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action