| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects with a type of blood cancer (multiple myeloma) that is either relapsed (comes back) or refractory (did not get better) after prior treatment. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| - To compare progression-free survival (PFS) in subjects with t(11;14)-positive MM treated with venetoclax in combination with dexamethasone versus pomalidomide in combination with dexamethasone. |
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| E.2.2 | Secondary objectives of the trial |
- To compare, between treatment arms (where applicable), the following:
● rate of very good partial response (VGPR) or better;
● overall response rate (ORR);
● patient reported outcomes (PRO) including Fatigue (Patient Reported Outcomes Measurement Information System
[PROMIS] Fatigue Short Form 7a), Worst Pain (Brief Pain Inventory – Short Form [BPI-SF]), Physical
Functioning (EORTC QLQ-C30), and Global Health Status/Quality of Life (EORTC QLQ-C30);
● overall survival (OS);
● duration of response (DOR);
● time to disease progression (TTP);
● time to response (TTR);
● minimal residual disease (MRD) negativity rate;
● pharmacokinetics of venetoclax,
● safety
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
- 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).
- 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 Eastern Cooperative Oncology Group (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.
- 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.
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|
| E.4 | Principal 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 or C infection based on screening blood testing;
• 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 parenteral 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 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 cytochromeP450 (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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- The primary efficacy endpoint is progression-free survival (PFS) per Independent Review Committee (IRC) based on IMWG criteria. PFS is defined as the time in days from subject randomization to the date of the first documented progressive disease (PD) or death due to any cause, whichever occurs first.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- PFS will be monitored throughout the study for PD or death whichever occurs first.
|
|
| E.5.2 | Secondary end point(s) |
- Secondary Endpoints are:
• Rate of very good partial response (VGPR) or better
• Overall response rate (ORR)
• Patient reported outcomes: Fatigue (PROMIS Fatigue Short Form 7a), Worst Pain (BPI-SF), Physical Functioning (EORTC QLQ-C30), and Global Heath Status/Quality of Life (EORTC QLQ-C30)
• Overall survival (OS)
• Duration of response (DOR)
• Time to disease progression (TTP)
• Time to response (TTR)
• Minimal residual disease (MRD) negativity rate
• Pharmacokinetics of venetoclax
• Safety
- Biomarker Samples will be collected to conduct exploratory investigations into known and/or novel biomarkers, including tumor BCL-2 family member expression, chromosomal abnormalities (gains, deletions, and/or mutations) and circulating markers of disease.
-Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiogram (ECG) variables, and clinical laboratory testing (hematology and chemistry)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Biomarker Research will be collected at specified timepoints and monitored throughout the study.
- PRO assessments will be collected at specified timepoints throughout the study.
- Safety evaluations will be monitored for the entire study duration of the study.
- PK samples for venetoclax will be evaluated for peak (i.e., 6 hour) and trough concentrations (Ctrough).
- Efficacy endpoints will be evaluated throughout the study.
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 118 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Denmark |
| European Union |
| Israel |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Singapore |
| Turkey |
| Ukraine |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end-of-study is defined as the last subject’s last visit, including survival. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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