Study of Melflufen (Melphalan Flufenamide) in Combination With Daratumumab in Relapsed-Refractory Multiple Myeloma (LIGHTHOUSE)

• ClinicalTrials.gov Identifier: NCT04649060
• Recruitment Status: Terminated
• First Posted: December 2, 2020
• Results First Posted: June 8, 2023
• Last Update Posted: June 8, 2023
• Sponsor: Oncopeptides AB
• Information provided by (Responsible Party): Oncopeptides AB

Tracking Information

• First Submitted Date: November 24, 2020
• First Posted Date: December 2, 2020
• Results First Submitted Date: February 7, 2023
• Results First Posted Date: June 8, 2023
• Last Update Posted Date: June 8, 2023
• Actual Study Start Date: December 21, 2020
• Actual Primary Completion Date: February 7, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 30, 2023)

Progression Free Survival (PFS) [ Time Frame: From the date of randomization until the end of study (approximately 12 months). ]

Time from the date of randomization to the date of first documentation of confirmed progressive disease (PD) or death due to any cause, whichever occurred first.

Original Primary Outcome Measures (submitted: November 24, 2020)

Progression Free Survival (PFS) [ Time Frame: 12 months ]

time from the date of randomization to the date of first documentation of confirmed progressive disease (PD) or death due to any cause

Current Secondary Outcome Measures (submitted: March 30, 2023)

• Overall Response Rate (ORR) [ Time Frame: From the date of randomization until the end of study (approximately 12 months). ]
  Proportion of patients who achieve a best-confirmed response of stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR).
• Duration of Response (DOR) [ Time Frame: From the date of randomization until the end of study (approximately 12 months). ]
  Time from the first evidence of confirmed assessment of sCR, CR, VGPR or PR to first confirmed disease progression, or death due to any cause. DOR is defined only for patients with a confirmed PR or better.
• Best Response [ Time Frame: From the date of randomization until the end of study (approximately 12 months). ]
  Proportion of patients with sCR, CR, VGPR, PR, Minimal Response (MR), Stable Disease (SD), PD, or non-evaluable (NE).
• Clinical Benefit Rate (CBR) [ Time Frame: From the date of randomization until the end of study (approximately 12 months). ]
  The proportion of patients who achieve a best confirmed response of sCR, CR, VGPR, PR, or MR.
• Duration of Clinical Benefit (DOCB) [ Time Frame: From the date of randomization until the end of study (approximately 12 months). ]
  Time from first evidence of confirmed assessment of sCR, CR, VGPR, PR, or MR to first confirmed disease progression, or to death due to any cause. DOCB is defined only for patients with a confirmed MR or better.
• Time to Response (TTR) [ Time Frame: From the date of randomization until the end of study (approximately 12 months). ]
  Time from randomization to the date of the first documented confirmed response in a patient who has responded with ≥PR.
• Time to Progression (TTP) [ Time Frame: From the date of randomization until the end of study (approximately 12 months). ]
  Time from randomization to the date of the first documented confirmed PD
• Time to Next Treatment (TTNT) [ Time Frame: From the date of randomization until the end of study (approximately 12 months). ]
  Time from randomization to the date of next anti-myeloma treatment or until death.
• Overall Survival (OS) [ Time Frame: From the date of randomization until the end of study (approximately 12 months). ]
  Time from randomization to death due to any cause.

Original Secondary Outcome Measures (submitted: November 24, 2020)

• Overall Response Rate (ORR) [ Time Frame: 12 months ]
  Proportion of patients who achieve a best confirmed response of stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR)).
• Duration of Response (DOR) [ Time Frame: 12 months ]
  time from the first evidence of confirmed assessment of sCR, CR, VGPR or PR to first confirmed disease progression, or death due to any cause. DOR is defined only for patients with a confirmed PR or better.
• Frequency and Grade of treatment emergent adverse events (TEAE). [ Time Frame: 13 months ]
  Serious Adverse Events will be collected from signing of the Informed Consent until 30 days after last dose of study treatment or initiation of subsequent therapy whichever occurs first. AEs will be collected from the start of study treatment until 30 days after the last dose of any study drug or initiation of subsequent therapy whichever occurs first.
• Best Response [ Time Frame: 12 months ]
  proportion of patients with sCR, CR, VGPR, PR, Minimal Response (MR), Stable Disease (SD), PD or non-evaluable.
• Clinical benefit rate (CBR) [ Time Frame: 12 months ]
  the proportion of patients who achieve a best confirmed response of sCR, CR, VGPR, PR or MR.
• Duration of Clinical Benefit (DOCB) [ Time Frame: 12 months ]
  (time from first evidence of confirmed assessment of sCR, CR, VGPR, PR, or MR to first confirmed disease progression, or to death due to any cause.) DOCB is defined only for patients with a confirmed MR or better.
• Time to response (TTR) [ Time Frame: 12 months ]
  Time from randomization to the date of the first documented confirmed response in a patient who has responded with ≥PR.
• Time to progression (TTP) [ Time Frame: 12 months ]
  Time from the date of randomization to the date of the first documented confirmed PD
• Time to next treatment (TTNT) [ Time Frame: 12 months ]
  Time from randomization to the date of next anti-myeloma treatment or until death.
• Overall survival (OS) [ Time Frame: 36 months (24 months follow-up after progression) ]
  time from date of randomization to death due to any cause

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Melflufen (Melphalan Flufenamide) in Combination With Daratumumab in Relapsed-Refractory Multiple Myeloma
• Official Title: A Randomized, Controlled, Open-Label Phase 3 Study of Melflufen in Combination With Daratumumab Compared With Daratumumab in Patients With Relapsed or Relapsed-Refractory Multiple Myeloma

Brief Summary

This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI.

Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking Description:

Independent Review Committee was planned to be blinded to treatment assignment. Due to the early termination, the response assessments were only done by investigators, not by an independent review committee.

Primary Purpose: Treatment

Condition

• Relapsed Multiple Myeloma
• Relapsed-Refractory Multiple Myeloma

Intervention

• Drug: Melflufen
  Powder for solution for i.v. infusion
  Other Names:

  • Melphalan Flufenamide
  • Pepaxto
  • Pepaxti
• Drug: Dexamethasone
  Oral tablets
  Other Name: Dex
• Drug: Daratumumab
  Solution for s.c. injection
  Other Name: Darzalex FASPRO

Study Arms

• Experimental: Arm A (melflufen+dexamethasone+daratumumab)

  Treatment was given in 28-day cycles in an outpatient treatment setting.

  • Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle
  • Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years)
  • Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7
  Interventions:

  • Drug: Melflufen
  • Drug: Dexamethasone
  • Drug: Daratumumab
• Active Comparator: Arm B (daratumumab)

  Treatment was given in 28-day cycles in an outpatient treatment setting.

  • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7

  Intervention: Drug: Daratumumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: February 16, 2022): 54
• Original Estimated Enrollment (submitted: November 24, 2020): 240
• Actual Study Completion Date: February 7, 2022
• Actual Primary Completion Date: February 7, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• A prior diagnosis of multiple myeloma with documented disease progression after the last line of therapy
• Double refractory to an IMiD and a PI (regardless of the number of prior lines of therapy) or have received at least 3 prior lines of therapy including an IMiD and a PI

• Prior treatment with daratumumab or another anti-CD38 antibody may be allowed under certain circumstances:

  • Achieved at least partial response (PR) and not refractory to an anti-CD38 antibody
  • At least 6 months since the last dose of anti-CD38 antibody
  • Not discontinued anti-CD38 antibody treatment due to related Grade ≥ 3 toxicity
• Male and female of childbearing potential agree to use contraception during the treatment period and at least 3 months after the last dose

Exclusion Criteria:

• Primary refractory disease (i.e., never responded with at least Minimal Response to any prior therapy for multiple myeloma)
• Prior treatment with CD38 CAR-T cell therapy or CD38/CD3 bispecific antibodies
• Any medical condition that may interfere with safety or participation in this study
• Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast, or very low and low-risk prostate cancer in active surveillance
• Known or suspected amyloidosis, plasma cell leukemia, or POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Known central nervous system (CNS) or meningeal involvement of myeloma
• Prior stem cell transplant (autologous and/or allogenic) within 6 months of initiation of therapy or prior allogeneic stem cell transplantation with active graft-versus-host-disease
• Prior treatment with melflufen

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Bulgaria, Czechia, Georgia, Germany, Greece, Norway, Poland, Russian Federation, Serbia, Spain, Ukraine
• Removed Location Countries: Hungary, Slovakia, United States

Administrative Information

• NCT Number: NCT04649060
• Other Study ID Numbers: OP-108; 2019-002161-36 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Oncopeptides AB
• Original Responsible Party: Same as current
• Current Study Sponsor: Oncopeptides AB
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Maria-Victorìa Mateos, MD, PhD; Complejo Hospitalario de Salamanca

• PRS Account: Oncopeptides AB
• Verification Date: February 2023