Phase 2 Open-Label Study of Venetoclax, Carfilzomib, and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients
- Trial ID
- 2023-505659-27-00
- Protocol
- M15-538
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2, open-label, multi-center study is to assess the **safety** and tolerability of venetoclax in combination with carfilzomib and dexamethasone in subjects with relapsed or refractory multiple myeloma (RRMM). Additionally, the study aims to evaluate the objective response rate (ORR) and very good partial response (VGPR) or better rate of the venetoclax, carfilzomib, and dexamethasone (VenKd) combination at the target dose in RRMM subjects, including those with t(11;14)-positive RRMM. The clinical relevance of these objectives lies in determining the potential of this combination therapy to provide a viable treatment option for patients with RRMM, a condition characterized by resistance to standard therapies.
Secondary objectives include:
- Investigating the International Myeloma Working Group (IMWG) response rates for subjects with high BCL-2 expression and those with prior exposure to lenalidomide.
- Assessing time-to-event endpoints such as 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.
- Characterizing the pharmacokinetics (PK) in plasma of venetoclax and carfilzomib.
- Assessing minimal residual disease (MRD) in the bone marrow using next-generation sequencing (NGS).
Participants
The clinical trial involves a total of **103 participants** diagnosed with **Multiple Myeloma**, specifically those with relapsed or refractory forms of the disease. The study population includes both male and female subjects, aged **18 years and older**, who have previously undergone treatment for Multiple Myeloma. Participants were selected based on their documented relapsed or progressive disease status, with a requirement for measurable disease at screening. The trial includes individuals with an **Eastern Cooperative Oncology Group (ECOG) performance score** of 2 or less, ensuring they are capable of self-care and ambulatory activities. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific contraceptive measures if of childbearing potential. The trial population includes a vulnerable group, indicating additional ethical considerations in the study design. Key inclusion criteria focus on prior treatment history and specific laboratory parameters, ensuring participants meet the necessary health standards for trial participation.
Plans and Procedures
The clinical trial is a **Phase 2, open-label, multi-center study** designed to evaluate the safety and efficacy of **venetoclax** in combination with **carfilzomib** and **dexamethasone** in subjects with relapsed or refractory **multiple myeloma**. The trial employs a non-randomized, open-label design, allowing for direct observation of the treatment effects without a placebo control. The study is expected to run from November 23, 2020, to January 21, 2028, with participant involvement lasting up to 2615 days, depending on individual response and tolerability.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as an **ECOG performance score** of ≤ 2, documented relapsed or progressive multiple myeloma, and specific laboratory parameters. Following successful screening, participants will receive the investigational treatment regimen. Regular follow-up visits will be scheduled to monitor safety, tolerability, and response to treatment, with assessments including **objective response rate (ORR)** and **very good partial response (VGPR)**. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and any adverse events.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial aims to provide comprehensive data on the combination therapy's safety profile and its potential to improve outcomes in this patient population. The study will also explore the pharmacokinetics of the drugs involved and assess minimal residual disease using next-generation sequencing. The trial's primary endpoints focus on safety and efficacy, while secondary endpoints include progression-free survival and overall survival metrics.
Treatment
The clinical trial involves the administration of **Venetoclax**, a chemical compound provided in the form of a **film-coated tablet**. Venetoclax is administered orally with a maximum daily dose of 800 mg. The total maximum dose over the treatment period is 1,924,608 mg. The treatment duration is set for a maximum of 2615 days. Venetoclax is produced by ABBVIE DEUTSCHLAND GMBH & CO. KG and is identified by the sponsor product code ABT-199. The medication is designated as an orphan drug, indicating its use in rare conditions.
**Dexamethasone** is utilized as a non-experimental treatment in this study. It is provided in the form of 4 mg tablets and is also administered orally. The maximum daily dose of dexamethasone is 40 mg, with a total maximum dose of 13,747.2 mg over the treatment period. The treatment duration is consistent with the other medications at 2615 days. Dexamethasone is manufactured by KRKA, D.D., NOVO MESTO and is not designated as an orphan drug.
**Carfilzomib**, marketed as Kyprolis, is another experimental medication used in this trial. It is supplied as a **powder for solution for infusion** and is administered intravenously. The maximum daily dose is 70 mg/m², with a total maximum dose of 18,043.2 mg/m² over the treatment period. The treatment duration is also set for a maximum of 2615 days. Carfilzomib is produced by AMGEN EUROPE B.V. and is designated as an orphan drug. Compliance with the dosing schedule and administration is monitored throughout the trial to ensure adherence to the protocol.
Efficacy
The efficacy of the combination treatment of **Venetoclax**, Carfilzomib, and Dexamethasone in subjects with relapsed or refractory multiple myeloma will be assessed through several key endpoints. The primary efficacy endpoints include the objective response rate (ORR) and the very good partial response (VGPR) or better rate, as well as the complete response (CR) or better rate, as defined by the International Myeloma Working Group (IMWG) response criteria. These endpoints will be evaluated in subjects receiving the target dose combination of Venetoclax, Carfilzomib, and Dexamethasone (VenKd), and specifically in those with t(11;14)-positive multiple myeloma.
Secondary efficacy endpoints will include the investigation of IMWG response rates in subjects with high BCL-2 expression and those with prior exposure to lenalidomide. Additionally, time-to-event endpoints such as progression-free survival (PFS), time to response (TTR), time to progression (TTP), duration of response (DOR), and overall survival (OS) will be assessed. Minimal residual disease (MRD) in the bone marrow will be evaluated using next-generation sequencing (NGS) to provide further insights into the efficacy of the treatment regimen.
The efficacy assessments will be conducted at various timepoints throughout the study, with specific intervals determined by the study protocol. The data collected will be analyzed to determine the effectiveness of the VenKd combination therapy in achieving the desired clinical outcomes in the study population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
- Subject has documented relapsed or progressive MM 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 t(11;14) positive as determined by an analytically validated FISH assay per study central laboratory testing.
- Subject has received prior treatment for MM. ● Parts 1, 2, and 3: At least 1 but no more than 3 prior lines of therapy ● Part 4: At least 1 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.
- 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.
- Subject must meet the following laboratory parameters within 14 days 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: ○ ≥ 50,000/mm3 for subject with ≤ 50% myeloma involvement in the bone marrow; ○ ≥ 30,000/mm3 for subject with > 50% myeloma involvement in the bone marrow; ○ 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 AbbVie TAMD or designee ● Creatinine clearance ≥ 30 mL/min measured by 24-hour urine collection or calculated using Cockcroft-Gault formula.
- Subject must be ≥ 18 years of age.
- Subject, or their legally authorized representative, 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.
- If female, subject is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation at least 3 months before study participation, bilateral oopho-rectomy and/or hysterectomy) or is of childbearing potential and is practicing an approved method of birth control throughout the study and 90 days after last dose of study drug. Examples of approved methods of birth control in this study include the following: ● Intrauterine device (IUD). ● Hormonal contraceptives (examples include birth control pills, vaginal rings, or patches), associated with inhibition of ovulation for at least 3 months prior to taking study drug. ● A vasectomized partner. ● Total abstinence from sexual intercourse with a male partner as the preferred lifestyle of the subject; periodic abstinence is not acceptable. Note: If male, subject agrees to follow one of the protocol-specified pregnancy avoidance measures below, including refraining from donating sperm, for up to 90 days post last dose of study drug. ● Surgically sterile (have had a vasectomy more than 6 months prior to screening). ● Subject using condom and female partner(s) using an approved method of contraception listed above. ● Total abstinence from sexual intercourse with a female partner as the preferred lifestyle of the subject; periodic abstinence is not acceptable.
- Females of childbearing potential must have negative results for pregnancy test performed: ● At Screening on a serum sample obtained within 28 days prior to randomization. ● Prior to dosing on a urine sample obtained on the first day of study drug administration, if it has been > 24 hours since obtaining the serum pregnancy test results. ● Females with documented non-childbearing potential (either postmenopausal or permanently surgically sterile as defined above) at Screening do not require pregnancy testing.
Exclusion Criteria
- 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) ● Known Human Immunodeficiency Virus (HIV) infection ● Known active SARS-CoV-2 infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection, they should undergo molecular (e.g., PCR) testing to rule out SARS-CoV-2 infection. If applicable, a negative test result is required prior to first dose. Subjects who do not meet SARS-CoV-2 eligibility criteria must be screen failed and may only rescreen after they meet the following SARS-CoV-2 viral clearance criteria below and do not have any other COVID-19 related medical condition that, in the opinion of the Investigator, would impact risk/benefit ratio of the subject's participation in the study: ○ At least 14 days since first PCR test result have passed in asymptomatic patients or 14 days since recovery, defined as resolution of fever without use of antipyretics and improvement in symptoms, or per institutional guidelines. ● Active hepatitis B or C infection based on screening blood testing ● Significant cardiovascular disease, including uncontrolled angina, hypertension (including uncontrolled hypertension defined as an average systolic blood pressure ≥ 160mm Hg or diastolic ≥ 100mm Hg despite optimal treatment),45 arrhythmia, recent myocardial infarction within 6 months of first dose, congestive heart failure (CHF) New York Heart Association (NYHA) Class ≥ 3, and/or left ventricular ejection fraction ≤ 40% as assessed by multiple gated acquisition scan (MUGA) or two dimensional (2D) echocardiogram (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 14 days 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
- 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, ● Adequately treated basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, ● Adequately treated 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.
- If subject had a prior allogeneic stem cell transplant (SCT), subject has evidence of ongoing graft-versus-host disease (GvHD).
- Subject has had prior treatment with carfilzomib, or has a hypersensitivity or allergy to any of the components of study therapy including captisol (a cyclodextrin derivative used to solubilize carfilzomib) or dexamethasone.
- Previous treatment with venetoclax or other BCL-2 inhibitor.
- 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.
- Subject who has consumed grapefruit products, Seville oranges (including marmalade containing Seville oranges), or starfruit within 3 days prior to study drug administration.
- Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the study or for approximately 90 days after the last dose of study drug.
- Male subject who is considering fathering a child or donating sperm during the study or for approximately 90 days after the last dose of study drug.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Hungary | Not Recruiting | 23 Nov 2020 | 14 |
 Spain | Not Recruiting | 23 Nov 2020 | 11 |
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 4 mg tablets | Comparator | TABLETS | ORAL | 40 | 2615 | PRD4715840 |
Kyprolis 60 mg powder for solution for infusion | Test | POWDER FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 70 | 2615 | PRD3374183 |
Venetoclax | Test | FILM-COATED TABLET | ORAL | 800 | 2615 | PRD2186236 |