| 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 |
|
| 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 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To assess the safety and tolerability of venetoclax in combination with carfilzomib and dexamethasone when administered in subjects with relapsed or refractory multiple myeloma (RRMM).
o assess the objective response rate (ORR) and very good partial response (VGPR) or better rate of venetoclax carfilzomib dexamethasone (VenKd) at the target dose combination in subjects with RRMM, and in t(11;14)-positive RRMM subjects.
- To explore and compare safety and preliminary efficacy of VenKd combination at 400 mg or 800 mg venetoclax dose levels with carfilzomib dexamethasone (Kd) (control) regimen. International Myeloma Working Group (IMWG) response rates (per investigator) including ORR, VGPR, or better rate, and complete response (CR) or better rate will be investigated.
|
|
| E.2.2 | Secondary objectives of the trial |
• To investigate the IMWG response rates for subjects with high BCL-2 expression, and for subjects with prior exposure to lenalidomide.
• To assess the time-to-event endpoints: progression-free survival (PFS), time to response (TTR), time to progression (TTP), duration of response (DOR), and overall survival (OS) of the VenKd combination in RRMM subjects.
• To characterize the pharmacokinetics (PK) in plasma of venetoclax and carfilzomib.
• To assess minimal residual disease (MRD) in the bone marrow by next generation sequencing (NGS).
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
2. Subject has documented RRMM on or after any regimen or is refractory to the most recent line of therapy.
- Relapsed myeloma is defined as previously treated myeloma that progresses and requires initiation of salvage therapy, but does not meet criteria for refractory myeloma.
- Refractory myeloma is defined as disease that is nonresponsive (failure to achieve minimal response or development of progressive disease [PD]) while on primary or salvage therapy, or progresses within 60 days of last therapy.
- For Part 4, subjects must meet the above criteria and also be positive for translocation t(11;14) as determined by an analytically validated Fluorescent In Situ Hybridization (FISH) assay per central laboratory testing.
3. Subject has received prior treatment with at least one prior line of therapy for MM.
- Parts 1, 2, 3: Subject has received prior treatment with one to three prior lines of therapy.
- Part 4: Subject has received prior treatment with at least one prior line of therapy.
- A line of therapy consists of ≥ 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens.
4. Subject has measurable disease at Screening, defined as at least one of the following:
- Serum M-protein ≥ 0.5 g/dL (≥ 5 g/L), OR
- Urine M-protein ≥ 200 mg/24 hours, OR
- Serum free light chain (FLC) ≥ 10 mg/dL, provided serum FLC ratio is abnormal.
5. Subject must meet the following laboratory parameters within 2 weeks prior to first dose, per laboratory reference range:
- Absolute neutrophil count (ANC) ≥ 1000/μL; subject may use growth factor support to achieve ANC eligibility criteria.
- Platelet count:
o ≥ 50,000/mm3 for subject with ≤ 50% myeloma involvement in the bone marrow;
o ≥ 30,000/mm3 for subject with > 50% myeloma involvement in the bone marrow;
o Subject 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 × ULN; subject with documented Gilbert's syndrome may have bilirubin > 1.5 × ULN with the approval of the Primary Therapeutic Area Medical Director.
- Creatinine clearance ≥ 30 mL/min, measured by 24-hour urine collection or calculated using the Cockcroft-Gault formula.
|
|
| E.4 | Principal exclusion criteria |
1. Subject has any of the following conditions:
- Non-secretory or oligo-secretory MM
- 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)
- Active hepatitis B or C infection based on screening blood testing
- Significant cardiovascular disease, including uncontrolled angina, hypertension, arrhythmia, recent myocardial infarction within 6 months of first dose, congestive heart failure New York Heart Association (NYHA) Class ≥ 3, and/or left ventricular ejection fraction ≤ 40% as assessed by multiple gated acquisition scan (MUGA) or ECHO.
- Major surgery within 4 weeks prior to first dose
- Acute infections requiring antibiotic, antifungal, or antiviral therapy within 14 days prior to first dose.
- Peripheral neuropathy ≥ Grade 3 or ≥ Grade 2 with pain within 2 weeks prior to first dose
- Uncontrolled diabetes or uncontrolled hypertension within 14 days prior to first dose
- Any other medical condition that, in the opinion of the Investigator, would adversely affect the subject's participation in the study.
2. Subject has a history of other active malignancies, including myelodysplastic syndrome (MDS), within the past 3 years prior to study entry, 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,
- Previous malignancy with no evidence of disease confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study.
3. If subject had a prior allogeneic stem cell transplant (SCT), subject has evidence of ongoing graft-versus-host disease (GvHD).
4. Subject has had prior treatment with carfilzomib or has a hypersensitivity or allergy to captisol (a cyclodextrin derivative used to solubilize carfilzomib) or dexamethasone.
5. Subject is refractory to any BCL-2 family inhibitor.
6. Subject has been treated or received any of the following:
- Allogeneic or syngeneic SCT within 6 months prior to first dose.
- Autologous SCT within 12 weeks prior to first dose.
- Immunization with live vaccine within 8 weeks prior to first dose.
- Monoclonal antibodies within 6 weeks prior to first dose.
- Any anti-myeloma therapy (other than monoclonal antibodies), including chemotherapy, radiotherapy, biological, immunotherapy or an investigational therapy, including targeted small molecule agents within 5 half-lives (or 14 days if half-life is unknown) prior to first dose.
- Corticosteroid therapy at a dose equivalent to ≥ 4 mg/day of dexamethasone within 3 weeks prior to first dose.
- A strong or moderate CYP3A inhibitor or inducer within 1 week prior to first dose.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
· To assess the safety and tolerability of venetoclax in combination with carfilzomib and dexamethasone when administered in subjects with relapsed or refractory multiple myeloma (RRMM).
· To assess the objective response rate (ORR) and very good partial response (VGPR) or better rate of venetoclax carfilzomib dexamethasone (VenKd) at the target dose combination in subjects with RRMM, and in t(11;14)-positive RRMM subjects.
·To explore and compare safety and preliminary efficacy of VenKd combination at 400 mg or 800 mg venetoclax dose levels with carfilzomib dexamethasone (Kd) (control) regimen. International Myeloma Working Group (IMWG) response rates (per investigator) including ORR, VGPR, or better rate, and complete response (CR) or better rate will be investigated.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
· Safety will be monitored throughout the subject’s participation in the study.
· IMWG response rates are dependent on the individual subject’s response to therapy. All subjects will be treated until progressive disease, unacceptable toxicity or other reason for discontinuation.
|
|
| E.5.2 | Secondary end point(s) |
· To investigate the IMWG response rates for subjects with high BCL-2 expression, and for subjects with prior exposure to lenalidomide.
· To assess the time-to-event endpoints: progression-free survival (PFS), time to response (TTR), time to progression (TTP), duration of response (DOR), and overall survival (OS) of the VenKd combination in RRMM subjects.
· To characterize the pharmacokinetics (PK) in plasma of venetoclax and carfilzomib.
· To assess minimal residual disease (MRD) in the bone marrow by next generation sequencing (NGS).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
· IMWG response rates are dependent on the individual subject’s response to therapy. All subjects will be treated until progressive disease, unacceptable toxicity or other reason for discontinuation.
· PFS will be monitored throughout the study for first documented progressive disease or death due to any cause, whichever comes first.
· Safety and biomarker research will be monitored throughout the subject’s participation in the study.
|
|
| 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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| Hungary |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
Print
