History of Changes for Study: NCT04122625

Study to Assess Safety and Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) Mimetic Debio 1143 (SMARTPLUS-106)

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Study Record Versions

Version	Submitted Date	Changes
1	October 9, 2019	None (earliest Version on record)
2	October 31, 2019	Study Status
3	November 27, 2019	Study Status
4	December 30, 2019	Study Status and Contacts/Locations
5	January 31, 2020	Contacts/Locations and Study Status
6	March 3, 2020	Study Status and Contacts/Locations
7	March 31, 2020	Contacts/Locations and Study Status
8	April 30, 2020	Study Status
9	May 31, 2020	Study Status
10	June 30, 2020	Study Status
11	July 31, 2020	Study Status and Contacts/Locations
12	August 28, 2020	Study Status and Study Design
13	September 20, 2020	Study Status
14	October 31, 2020	Study Status
15	November 30, 2020	Study Status
16	December 30, 2020	Study Status
17	January 29, 2021	Study Status
18	February 27, 2021	Study Status
19	March 30, 2021	Study Status
20	April 29, 2021	Study Status
21	May 27, 2021	Study Status
22	June 28, 2021	Study Status
23	July 26, 2021	Study Status
24	August 25, 2021	Study Status
25	September 22, 2021	Study Status
26	October 21, 2021	Recruitment Status, Study Status and Contacts/Locations
27	November 22, 2021	Study Status
28	December 23, 2021	Study Status
29	January 21, 2022	Study Status
30	February 22, 2022	Study Status
31	March 30, 2022	Study Status
32	April 29, 2022	Recruitment Status, Study Status and Study Design
33	April 5, 2023	Quality Control Review has not concluded Returned: April 26, 2023 Outcome Measures, Arms and Interventions, Study Status, Document Section, IPDSharing, Eligibility and Study Design
34	May 17, 2023	Outcome Measures, Study Status

Comparison Format:

Merged
Side-by-Side

Study Identification


Unique Protocol ID:	Debio 1143-106
Brief Title:	Study to Assess Safety and Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) Mimetic Debio 1143 (SMARTPLUS-106)
Official Title:	A Dose-optimization, Exploratory Phase Ib/II Study to Assess Safety and Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) Mimetic Debio 1143, When Given in Combination With the Anti-PD-1 Antibody Nivolumab in Patients With Specific Solid Tumors Who Have Progressed During or Immediately After Anti-PD-1/PD-L1 Treatment
Secondary IDs:	2018-003546-16 [EudraCT Number]

Study Status


Record Verification:	October 2019
Overall Status:	Recruiting
Study Start:	May 9, 2019
Primary Completion:	January 20, 2023 [Anticipated]
Study Completion:	January 20, 2023 [Anticipated]

First Submitted:	August 30, 2019
First Submitted that Met QC Criteria:	October 9, 2019
First Posted:	October 10, 2019 [Actual]

Last Update Submitted that Met QC Criteria:	October 9, 2019
Last Update Posted:	October 10, 2019 [Actual]

Sponsor/Collaborators


Sponsor:	Debiopharm International SA
Responsible Party:	Sponsor
Collaborators:

Oversight


U.S. FDA-regulated Drug:	Yes
U.S. FDA-regulated Device:	No
Data Monitoring:	Yes

Study Description

Brief Summary:

Part A (dose-optimization)- to determine the recommended phase 2 dose (RP2D) taking into account dose-limiting toxicity (DLT/s) in Cycle 1, overall safety/tolerability and pharmacokinetic (PK), by optimizing doses of Debio 1143 when combined with the standard dose of nivolumab, as well as treatment compliance in participants with advanced solid malignancies who failed prior systemic standard treatments.

Part B (basket trial)- to evaluate the preliminary anti-tumor activity of Debio 1143 at the RP2D in combination with nivolumab at the standard dose, overall and in each participant cohort (Cohort 1: small cell lung cancer [SCLC]; Cohort 2: squamous cell carcinoma of the head and neck [SCCHN]; Cohort 3: gastrointestinal (GI) cancers with known microsatellite instability-high/mismatch repair deficiency (MSI-H/MMRd) or other deoxyribonucleic acid (DNA) damage repair (DDR) abnormalities, including homologous recombination deficiency (HRD); Cohort 4: platinum-resistant epithelial ovarian cancer [EOC], endometrial cancer, primary peritoneal cancer (PPC) or cervical cancer, with known MSIH/MMRd, hereditary/somatic mutations of the breast cancer 1 (BRCA1) and BRCA2 genes or other DNA DDR abnormalities (incl. HRD).

Detailed Description:

Conditions


Conditions:	Solid Tumor
Keywords:

Study Design


Study Type:	Interventional
Primary Purpose:	Treatment
Study Phase:	Phase 1/Phase 2
Interventional Study Model:	Sequential Assignment
Number of Arms:	1
Masking:	None (Open Label)
Enrollment:	72 [Anticipated]

Arms and Interventions

Arms

Assigned Interventions

Experimental: Debio 1143 + Nivolumab

Part A: Participants will receive Debio 1143 at a starting dose of 150 milligrams (mg) orally once daily on Days 1-10 and Days 15-24 every 4 weeks (q4w) along with nivolumab at a flat dose of 240 mg intravenously (IV) on Days 1 and 15 of a 28-day cycle, participants may be switched to 480 mg IV on Day 1 q4w, exclusively upon investigator request with the sponsor agreement. Part B: Participants will receive Debio 1143 at RP2D established in Part A in combination with nivolumab as per standard care.

Drug: Debio 1143

Debio 1143 will be administered capsule orally once daily for 10 consecutive days every 2 weeks and Days 15-24 q4w. The dose of Debio 150 mg can be escalated to 200 in Part A and it is to be decided in Part B.

Drug: Nivolumab

Nivolumab will be administered as 240 mg IV infusion on Days 1 and 15 of a 28-day cycle.

Outcome Measures


Primary Outcome Measures:
1.	Part A: Recommended Phase 2 Dose (RP2D) of Debio1143 [ Time Frame: Up to 28 days (Cycle 1) ]
2.	Part B: Confirmed Objective Response Rate (ORR) [ Time Frame: From first occurrence of objective response until disease progression or death from any cause or end of study (Up to 17 months) ]
Secondary Outcome Measures:
1.	Part A and B: Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Laboratory Abnormalities [ Time Frame: Up to 17 months ]
2.	Part A and B: Number of Participants with Change in Weight [ Time Frame: Up to 17 months ]
3.	Part A and B: Number of Participants with Change in Vital Signs [ Time Frame: Up to 17 months ]
4.	Part A and B: Number of Participants with Change in Temperature [ Time Frame: Up to 17 months ]
5.	Part A and B: Number of Participants with Change in Electrocardiogram (ECG) [ Time Frame: Up to 17 months ]
6.	Part A and B: Number of Participants with Change in Eastern Cooperative Oncology Group performance status (ECOG-PS) [ Time Frame: Up to 17 months ]
7.	Part A and B: Number of Participants Leading to Treatment Discontinuations and Treatment Modifications due to AEs and Laboratory Abnormalities [ Time Frame: Up to 17 months ]
8.	Part A: Confirmed Objective Response Rate (ORR) [ Time Frame: From first occurrence of objective response until disease progression or death from any cause or end of study (Up to 17 months) ]
9.	Part A and B: Unconfirmed Objective Response Rate (ORR) [ Time Frame: From first occurrence of objective response until disease progression or death from any cause or end of study (Up to 17 months) ]
10.	Part A and B: Disease Control Rate (DCR) [ Time Frame: From the start of study treatment until disease progression/recurrence or analysis cut-off, whichever occurs first (Up to 17 months) ]
11.	Part A and B: Time to Response (TTR) [ Time Frame: From the date of first dose to the date of the first documented evidence of response (Up to 17 months) ]
12.	Part A and B: Duration of Response (DOR) [ Time Frame: From the time of documentation of response to disease progression or analysis cut-off date, which-ever occur first (Up to 17 months) ]
13.	Part A and B: Progression Free Survival (PFS) [ Time Frame: From the start of study treatment until disease progression/recurrence or death from any cause, whichever occurs first (Up to 17 months) ]
14.	Part A and B: Percentage of Participants with PFS at Month 6, 12 and 18 [ Time Frame: Month 6, 12 and 18 ]
15.	Part A and B: Overall Survival (OS) [ Time Frame: From the start of study treatment until death from any cause, whichever occurs first (Up to 17 months) ]
16.	Part A and B: OS Rate at Month 12 and 18 [ Time Frame: Month 12 and 18 ]
17.	Part A and B: Area Under the Curve (AUC) of Debio 1143 and Debio 1143-MET1 [ Time Frame: Part A: Day 1, 3, 8, 15, 17, 22 Cycle 1 (each cycle is 28 days); Day 1, 3, 15, 17 Cycle 3; Day 1 Cycle 6. Part B: Day 1, 8, 15, 22 Cycle 1; Day 1, 15, Cycle 3; Day 1 Cycle 6; End of Treatment (Up to 17 months) ]
18.	Part A and B: Maximum Observed Concentration (Cmax) of Debio 1143 and Debio 1143-MET1 [ Time Frame: Part A: Day 1, 3, 8, 15, 17, 22 Cycle 1 (each cycle is 28 days); Day 1, 3, 15, 17 Cycle 3; Day 1 Cycle 6. Part B: Day 1, 8, 15, 22 Cycle 1; Day 1, 15, Cycle 3; Day 1 Cycle 6; End of Treatment (Up to 17 months) ]
19.	Part A and B: Trough Concentration (Cmin) of Debio 1143 and Debio 1143-MET1 [ Time Frame: Part A: Day 1, 3, 8, 15, 17, 22 Cycle 1 (each cycle is 28 days); Day 1, 3, 15, 17 Cycle 3; Day 1 Cycle 6. Part B: Day 1, 8, 15, 22 Cycle 1; Day 1, 15, Cycle 3; Day 1 Cycle 6; End of Treatment (Up to 17 months) ]
20.	Part A and B: Serum Concentration of Nivolumab [ Time Frame: Part A: Day 1, 3, 8, 15, 17, 22 Cycle 1 (each cycle is 28 days); Day 1, 3, 15, 17 Cycle 3; Day 1 Cycle 6. Part B: Day 1, 8, 15, 22 Cycle 1; Day 1, 15, Cycle 3; Day 1 Cycle 6; End of Treatment (Up to 17 months) ]

Eligibility


Minimum Age:	18 Years
Maximum Age:
Sex:	All
Gender Based:
Accepts Healthy Volunteers:	No
Criteria:	Inclusion Criteria: Have received at least one prior line of standard systemic chemotherapy in the advanced/unresectable cancer setting (standard adjuvant/neoadjuvant treatment is acceptable if relapse occurred within six months of treatment end) Have progressed or relapsed during or after a prior anti-programmed cell death-1 (PD-1)/ programmed cell death-ligand 1 (PD-L1)-based treatment, given either as a single agent or in combination with standard/approved chemotherapy, tyrosine kinase inhibitors (TKIs), radiotherapy (RT) or other monoclonal antibodies (mAbs) that are not known to modulate/inhibit immune checkpoints (CPIs) Measurable disease (Part B only) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or Gynecologic Cancer Intergroup (GCIG) criteria in Cohort #4 (if applicable) and documented PD during or after prior PD-1/PD-L1 based therapy Exclusion Criteria: Thoracic or head and neck radiation >30 gray (Gy) within the 3 months prior to Cycle 1 Day 1 (C1D1) Have received, in total, more than 3 (i.e. Cohorts 1&2) or 4 (i.e. Cohorts 3&4) lines of prior systemic treatments (including adjuvant or neoadjuvant regimens if relapse within six months prior to C1D1) Liver cirrhosis Child-Pugh score B or C

Contacts/Locations


Central Contact Person:	Debiopharm International S.A Telephone: +41 21 321 01 11 Email: clinicaltrials@debiopharm.com
Locations:	France
	Centre Leon Berard [Recruiting] Lyon, France, 69008
	Institut Universitaire du Cancer de Toulouse Oncopole [Recruiting] Toulouse, France, 31100
	Institut Gustave Roussy [Recruiting] Villejuif, France, 94800
	Spain
	Hospital Vall d'Hebron [Recruiting] Barcelona, Spain, 08035
	START Madrid, Fundacion Jimenez Diaz [Recruiting] Madrid, Spain, 28040
	START Madrid, H.U. Sanchinarro [Recruiting] Madrid, Spain, 28050

IPDSharing


Plan to Share IPD:

References


Citations:
Links:
Available IPD/Information: