Phase 3 Multicenter Randomized Open-Label Study of Venetoclax and Dexamethasone Versus Pomalidomide and Dexamethasone in t(11;14)-Positive Relapsed/Refractory Multiple Myeloma
- Trial ID
- 2023-506112-40-00
- Protocol
- M13-494
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare **progression-free survival** (PFS) in subjects with t(11;14)-positive relapsed or refractory multiple myeloma (R/R Multiple Myeloma) treated with **venetoclax** in combination with **dexamethasone** versus **pomalidomide** in combination with dexamethasone. This objective is clinically relevant as PFS is a critical endpoint in oncology trials, reflecting the time during which a patient's disease does not worsen, thus providing insights into the efficacy of the treatment regimens.
The secondary objectives are to compare, between treatment arms, the following:
- Overall response rate (ORR)
- Rate of very good partial response (VGPR) or better per International Myeloma Working Group (IMWG) criteria
- Overall survival (OS)
- Minimal residual disease (MRD) negativity rate
- Patient-reported outcomes (PROs) evaluated using Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form (SF) 7a, Brief Pain Inventory – Short Form (BPI-SF), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) MM Module 20 (EORTC QLQ-MY20), and EORTC QLQ Core 30 (EORTC QLQC30)
- Duration of response (DOR)
- Time to disease progression (TTP)
- Time to response (TTR)
- Pharmacokinetics (PK) of venetoclax
- Safety
Participants
The clinical trial involves a total of **171 participants** diagnosed with **relapsed/refractory multiple myeloma**. The study population includes both male and female adults aged 18 years and older. Participants were selected based on specific inclusion criteria, including a documented diagnosis of multiple myeloma with t(11;14) positivity, and a history of at least two prior lines of therapy. The trial population is characterized by a requirement for measurable disease at screening and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Participants must have demonstrated disease progression on or within 60 days of their last therapy. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, as participants must be capable of providing informed consent and not be incarcerated. The selection process ensures that participants are willing and able to comply with the study protocol, including receiving antithrombotic prophylactic treatment and practicing specified methods of contraception if applicable.
Plans and Procedures
The clinical trial is a **Phase 3**, multicenter, randomized, open-label study designed to evaluate the efficacy of **venetoclax** in combination with **dexamethasone** compared to **pomalidomide** and dexamethasone in subjects with t(11;14)-positive relapsed or refractory **multiple myeloma**. The primary objective is to compare progression-free survival (PFS) between the two treatment groups. The trial is expected to run from November 5, 2019, to August 6, 2026, with participants involved for a maximum treatment period of 48 weeks.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, including laboratory values and previous treatment history. Following randomization, participants will attend regular follow-up visits to monitor treatment response, safety, and any adverse events. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to evaluate the overall response and progression of the disease.
Inclusion criteria require participants to have a documented diagnosis of multiple myeloma, an ECOG performance status of ≤2, and measurable disease at screening. Participants must have received at least two prior lines of therapy and be relapsed/refractory to lenalidomide. Exclusion criteria are not explicitly detailed in the provided data. Participants may be terminated early from the study if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it necessary for safety reasons.
The trial will assess several secondary endpoints, including overall response rate, overall survival, and minimal residual disease negativity rate. Safety and pharmacokinetics of venetoclax will also be evaluated. The study is not categorized as low intervention, and it involves the use of chemical medicinal products administered orally. The trial is conducted under the approval of an Independent Ethics Committee (IEC) or Institutional Review Board (IRB), ensuring compliance with ethical standards.
Treatment
The clinical trial involves the administration of several **experimental medications**. **Dexamethasone**, identified by the active substance **betamethasone sodium phosphate**, is administered in an oral pharmaceutical form coded as PHF00231MIG. The maximum daily dose is 40 mg, with a total maximum dose of 8320 mg over a treatment period of 48 weeks. This medication is not a pediatric formulation and is classified under the ATC code H02AB02. The administration route is oral, and participant compliance is monitored throughout the trial.
**Pomalidomide** is another experimental medication used in the trial, available in hard capsule form with varying dosages of 1 mg, 2 mg, 3 mg, and 4 mg. The maximum daily dose for pomalidomide is 4 mg, with a total maximum dose of 4032 mg over 48 weeks. This medication is also administered orally and is not a pediatric formulation. Pomalidomide is classified under the ATC code L04AX06 and is designated as an orphan drug. The manufacturer is Bristol-Myers Squibb Pharma EEIG.
**Venetoclax**, marketed under the sponsor product code ABT-199, is provided in a film-coated tablet form. The maximum daily dose is 800 mg, with a total maximum dose of 1168000 mg over the 48-week treatment period. Venetoclax is administered orally and is classified as an orphan drug. The manufacturer is AbbVie Deutschland GmbH & Co. KG. Compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol.
In this study, the experimental medications are compared against each other in terms of efficacy and safety. The trial aims to evaluate the progression-free survival in subjects with t(11;14)-positive relapsed or refractory multiple myeloma, treated with venetoclax in combination with dexamethasone versus pomalidomide in combination with dexamethasone. No placebo or standard-of-care therapy is used as a comparator in this trial. All medications are administered orally, and participant compliance is closely monitored to ensure accurate data collection and analysis.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the endpoint of **progression-free survival (PFS)**, as determined by an Independent Review Committee (IRC) based on the International Myeloma Working Group (IMWG) criteria. PFS is defined as the time from subject randomization to the first documented occurrence of progressive disease or death from any cause. Secondary efficacy endpoints include the overall response rate (ORR), the rate of very good partial response (VGPR) or better, overall survival (OS), and the minimal residual disease (MRD) negativity rate. Additional secondary endpoints involve the time to deterioration in disease symptoms and physical functioning, as measured by the EORTC QLQ-MY20 and EORTC QLQ-C30, respectively. Other patient-reported outcomes (PROs) will be assessed using instruments such as the PROMIS Fatigue Short Form 7a, Brief Pain Inventory – Short Form (BPI-SF), EuroQoL 5 Dimension 5 Level (EQ5D5L), and remaining domains of EORTC QLQ-MY20 and EORTC QLQ-C30.
The trial will also evaluate the duration of response (DOR), time to disease progression (TTP), time to response (TTR), and pharmacokinetics of venetoclax. Safety assessments will be conducted throughout the trial. The study is designed to compare the efficacy of venetoclax in combination with dexamethasone versus pomalidomide in combination with dexamethasone in subjects with t(11;14)-positive relapsed or refractory multiple myeloma. The trial is a Phase 3, multicenter, randomized, open-label study, with an estimated end date of August 6, 2026.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subjects must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
- Subject must have received at least 2 consecutive cycles of lenalidomide and be relapsed/refractory to lenalidomide as defined by one of the following: Subject experienced PD on or within 60 days of completing treatment. Subject exhibited PR or better but relapsed within 6 months after stopping treatment.
- Subject must have received at least 2 consecutive cycles of a proteasome inhibitor (bortezomib, carfilzomib or ixazomib).
- Subject has measurable disease at Screening, defined by at least 1 of the following: Serum M-protein ≥0.5 g/dL (≥5 g/L); OR Urine M-protein ≥200 mg/24 hours; OR Involved serum immunoglobulin free light chain (FLC) ≥10 mg/dL (100 mg/L), provided serum FLC ratio is abnormal
- Subject has MM positive for t(11;14) as determined by an analytically validated FISH assay per centralized laboratory testing.
- A negative serum pregnancy test for all female subjects (except those of non-childbearing potential) within 10 to 14 days prior to initiating therapy and a negative urine pregnancy test within 24 hours for all female subjects (except those of non-childbearing potential) at baseline prior to the first dose of study drug.
- If female, subject must be either postmenopausal, OR permanently surgically sterile OR for women of childbearing potential practicing at least 2 protocol-specified methods of birth control that are effective from at least 30 days before starting study drugs through at least 30 days after the last dose of any study drug.
- If male, and subject is sexually active with female partner(s) of childbearing potential, he must agree, from Study Day 1 through 30 days after the last dose of study drug, to practice the protocol-specified contraception.
- Adult male or female subjects ≥18 years old.
- Subjects should have laboratory values meeting the following criteria within the screening period prior to the first dose of study drug: Absolute neutrophil count (ANC) ≥1000/μL; subject may use growth factor support to achieve ANC eligibility criteria; Platelets: ≥50,000/mm3. For subjects with > 50% myeloma involvement in the marrow, a platelet count of ≥30,000 mm3. Subjects may not have received a platelet transfusion within 72 hours prior to the platelet count used for eligibility; Hemoglobin ≥8.0 g/dL; subject may receive red blood cell (RBC) transfusions in accordance with institutional guidelines to meet this criteria; AST and ALT ≤3 × upper limit of normal (ULN); Total bilirubin ≤1.5 x ULN (subjects with documented Gilbert's syndrome, may have bilirubin > 1.5 × ULN); Creatinine clearance ≥30 mL/min, measured by 24-hour urine collection or calculated using the Cockcroft-Gault formula); Serum calcium corrected for albumin ≤14.0 mg/dL (≤3.5 mmol/L) or ionized calcium (≤6.5mg/dL (≤1.6mmol/L).
- Subjects should be willing or able to comply with procedures required in this protocol.
- Subjects should be willing and able to receive antithrombotic prophylactic treatment.
- Documented diagnosis of multiple myeloma based on standard IMWG criteria.
- Subject has an ECOG performance status ≤ 2
- Subject has documented disease progression on or within 60 days of completion of their last therapy.
- Subject has received at least 2 prior lines of therapy. A line of therapy consists of at least 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens.
- Subjects must not be incarcerated and must be freely willing and able to provide informed consent (e.g., adults under legal protection measure [e.g., under guardianship/curatorship] or unable to express their consent and select adults under psychiatric care). Investigator's discretion should be applied.
Exclusion Criteria
- Subject has history of treatment with venetoclax or another BCL-2 inhibitor or pomalidomide.
- Subject has a history of other active malignancies, including myelodysplastic syndromes (MDS), within the past 3 years with the following exceptions: Adequately treated in situ carcinoma of the cervix uteri or the breast; Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment; or Previous malignancy with no current evidence of disease, and which was confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study.
- Subject has evidence of ongoing graft-versus-host disease (GvHD) if prior stem cell transplant (SCT).
- Subject must not have received any live vaccines within 8 weeks prior to randomization
- Subject has had prior treatment with the following: Allogeneic or syngeneic SCT within 16 weeks prior to randomization; or Autologous SCT within 12 weeks prior to randomization
- Subject has known central nervous system involvement of multiple myeloma.
- Subject has a history of clinically significant renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, pulmonary or hepatic disease within the last 6 months that, in the opinion of the investigator, would adversely affect participation in this study.
- Subject has a history of known allergies, hypersensitivities, or intolerance to any of the study drug or excipients, or thalidomide derivatives.
- Subject has the following conditions: Nonsecretory multiple myeloma; Active plasma cell leukemia i.e., either 20% of peripheral white blood cells or > 2.0 × 109/L circulating plasma cells by standard differential; Waldenström's macroglobulinemia; Primary amyloidosis; POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes); Known human immunodeficiency virus (HIV) infection; Active hepatitis B (hepatitis B surface antigen [HBsAg] positive) or C infection based on screening central laboratory blood testing at screening; Significant cardiovascular disease, including uncontrolled angina, arrhythmia, recent myocardial infarction within 6 months prior to first dose, congestive heart failure NYHA Class ≥3; Major surgery within 4 weeks prior to first dose or planned during study participation; Acute infections within 14 days prior to first dose requiring therapy (antibiotic, antifungal, or antiviral); Uncontrolled diabetes or hypertension within 14 days prior to first dose; or Peripheral neuropathy ≥Grade 3 or ≥Grade 2 with pain within 2 weeks prior to first dose.
- Female who is pregnant, breastfeeding, or considering becoming pregnant during the study and for at least 30 days after the last dose of study drug.
- Male who is considering fathering a child or donating sperm and/or semen during the study and for at least 30 days after the last dose of study drug.
- Subject who have been treated with any systemic anti-myeloma therapies within 5 half-lives or 2 weeks prior to randomization, whichever is longer (or 2 weeks if half-life unknown), and through the last dose of any study drug.
- Subject who have been treated with anti-myeloma radiotherapy within 2 weeks prior to randomization.
- Subject who have received corticosteroid therapy at a dose equivalent to > 4 mg daily of dexamethasone or a single dose of corticosteroid equivalent dose > 40 mg of dexamethasone within 2 weeks prior to randomization.
- Subject who have used systemic strong or moderate inhibitor or inducer of cytochrome P450 (CYP) 3A within 1 week prior to the first dose of study drugs.
- Subject who have used systemic strong inhibitor of CYP1A2 within 1 week prior to first dose.
- Subject who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or starfruit within 3 days prior to first dose.
- Subject who anticipate the use of prohibited medications or foods during study participation.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 05 Nov 2019 | 11 |
 Denmark | Not Recruiting | 05 Nov 2019 | 6 |
 France | Not Recruiting | 05 Nov 2019 | 10 |
 Germany | Not Recruiting | 05 Nov 2019 | 19 |
 Greece | Not Recruiting | 05 Nov 2019 | 14 |
 Italy | Not Recruiting | 05 Nov 2019 | 15 |
 Spain | Not Recruiting | 05 Nov 2019 | 16 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DEXAMETHASONE | Other | PHF00231MIG | ORAL | 40 | 48 | SCP1977137 |
Imnovid 3 mg hard capsules | Test | HARD CAPSULES | ORAL | 4 | 48 | PRD9260806 |
Imnovid 2 mg hard capsules | Test | HARD CAPSULES | ORAL | 4 | 48 | PRD9260805 |
Imnovid 4 mg hard capsules | Test | HARD CAPSULES | ORAL | 4 | 48 | PRD9260808 |
Venetoclax | Test | FILM-COATED TABLET | ORAL | 800 | 48 | PRD2186236 |
Imnovid 1 mg hard capsules | Test | HARD CAPSULES | ORAL | 4 | 48 | PRD9260804 |