A Study of Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly-Diagnosed Multiple Myeloma (ADVANCE)

• ClinicalTrials.gov Identifier: NCT04268498
• Recruitment Status: Recruiting
• First Posted: February 13, 2020
• Last Update Posted: June 11, 2021
• Sponsor: University of Miami
• Collaborator: Amgen
• Information provided by (Responsible Party): University of Miami

Study Description

Brief Summary:

This study is being done to find out whether carfilzomib, lenalidomide, and dexamethasone (KRD) or KRD and Daratumumab (KRD+DARA) might be safer and more effective ways of controlling multiple myeloma than the stand or care treatment, which is lenalidomide, bortexomib, and dexamethasone (VRD).

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma	Drug: Bortezomib; Drug: Dexamethasone; Drug: Lenalidomide; Drug: Acetaminophen; Drug: Diphenhydramine; Drug: Montelukast; Drug: Carfilzomib; Drug: Daratumumab; Biological: Autologous Stem Cell Transplant (ASCT)	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 462 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2, Open-Label Randomized Study of Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone vs Carfilzomib, Lenalidomide, and Dexamethasone vs Bortezomib, Lenalidomide, and Dexamethasone in Patients With Newly-Diagnosed Multiple Myeloma
• Actual Study Start Date: February 11, 2020
• Estimated Primary Completion Date: February 1, 2022
• Estimated Study Completion Date: February 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A - Bortezomib, Lenalidomide and Dexamethasone (VRD); Participants in this group will receive Bortezomib, Lenalidomide and Dexamethasone on a 21 day treatment cycle. Participants achieving a PR or better at the end of 4 cycles will continue to receive a total of 8 cycles of combination therapy. Participants with less than PR after completing 4 cycles will go off study therapy. After 8 cycles of therapy, participants who are MRD positive will have the option to receive an ASCT if stem cells were able to be extracted, before initiating maintenance therapy with Lenalidomide for up to 2 years, and patients who are MRD negative will go directly on to receive maintenance therapy with Lenalidomide for up to 2 years.	Drug: Bortezomib; 1.3 mg/m2 administered Subcutaneous (SC) or intravenous (IV) on days 1, 4, 8 and 11 of a 21 day treatment cycle for participants randomized to Arm A.; Drug: Dexamethasone; 20 mg or 40 mg per dose administered by mouth (PO) or IV. Participants randomized in Arm A: 20 mg/dose on days 1, 4, 8 and 11 on a 21 day treatment cycle; Participants randomized in Arm B: Cycles 1 through 4 - 40mg/dose on days 1, 8 and 15 on a 28 day cycle; Cycles 5 through 8 - 20mg/dose on days 1, 8, 15 on a 28 day cycle Participants randomized in Arm C: Cycle 1 - 20 mg/dose on days 1, 2, and 22, and 40mg/dose on days 8 and 15 on a 28 day cycle; Cycle 2 - 40 mg/dose on days 1, 8, and 15 and 20mg/dose o day 22 on a 28 day cycle; Cycles 3-4 - 40mg/dose on Days 1, 8, 15 on a 28 day cycle; Cycles 5-8 - 20mg/dose on days 1, 8, 15 on a 28 day cycle; Drug: Lenalidomide; 10 or 25 mg/day capsules administered PO. Participants randomized in Arm A: 25 mg/day capsules on Days 1 through 14 of a 21 day cycle.; Participants randomized in Arm B: Cycles 1 through 8 - 25 mg/day capsules on Days 1 through 21 of a 28 day cycle; Participants randomized in Arm C: Cycles 1 - 25 mg/day capsules on Days 2 through 21 of a 28 day cycle; Cycles 2 through 8 - 25 mg/day capsules on Days 1 through 21 of a 28 day cycle; Maintenance Therapy: 10 mg capsules on Days 1 through 21 on a 28 days cycle.; Other Name: Revlimid; Biological: Autologous Stem Cell Transplant (ASCT); Participants who are MRD positive at the conclusion of 8 cycles of study treatment, and were able to have their stem cells that were extracted, will receive ASCT from participants' bone marrow samples.
Experimental: Arm B - Carfilzomib, Lenalidomide and Dexamethasone (KRD); Participants in this group will receive Carfilzomib, Lenalidomide and Dexamethasone on a 28 day cycle. Participants achieving a PR or better at the end of 4 cycles will continue to receive a total of 8 cycles of combination therapy. Participants with less than PR after completing 4 cycles will go off study therapy. After 8 cycles of therapy, participants who are MRD positive will have the option to receive an ASCT if stem cells were able to be extracted, before initiating maintenance therapy with Lenalidomide for up to 2 years, and patients who are MRD negative will go directly on to receive maintenance therapy with Lenalidomide for up to 2 years.	Drug: Dexamethasone; 20 mg or 40 mg per dose administered by mouth (PO) or IV. Participants randomized in Arm A: 20 mg/dose on days 1, 4, 8 and 11 on a 21 day treatment cycle; Participants randomized in Arm B: Cycles 1 through 4 - 40mg/dose on days 1, 8 and 15 on a 28 day cycle; Cycles 5 through 8 - 20mg/dose on days 1, 8, 15 on a 28 day cycle Participants randomized in Arm C: Cycle 1 - 20 mg/dose on days 1, 2, and 22, and 40mg/dose on days 8 and 15 on a 28 day cycle; Cycle 2 - 40 mg/dose on days 1, 8, and 15 and 20mg/dose o day 22 on a 28 day cycle; Cycles 3-4 - 40mg/dose on Days 1, 8, 15 on a 28 day cycle; Cycles 5-8 - 20mg/dose on days 1, 8, 15 on a 28 day cycle; Drug: Lenalidomide; 10 or 25 mg/day capsules administered PO. Participants randomized in Arm A: 25 mg/day capsules on Days 1 through 14 of a 21 day cycle.; Participants randomized in Arm B: Cycles 1 through 8 - 25 mg/day capsules on Days 1 through 21 of a 28 day cycle; Participants randomized in Arm C: Cycles 1 - 25 mg/day capsules on Days 2 through 21 of a 28 day cycle; Cycles 2 through 8 - 25 mg/day capsules on Days 1 through 21 of a 28 day cycle; Maintenance Therapy: 10 mg capsules on Days 1 through 21 on a 28 days cycle.; Other Name: Revlimid; Drug: Carfilzomib; 20 mg or 56 mg/m2 per dose administered via IV. Participants randomized to Arm B: Cycle 1 - 20 mg/m2 per dose on Day 1 and 56 mg/m2 per dose on days 8 and 15 of a 28 day cycle; Cycles 2 through 8 - 56 mg/m2 per dose on days 1, 8 and 15 of a 28 day cycle; Participants randomized to Arm C: Cycle 1 - 20 mg/m2 per dose on Day 2 and 56 mg/m2 per dose on days 8 and 15 of a 28 day cycle; Cycles 2 through 8 - 56 mg/m2 per dose on days 1, 8 and 15 of a 28 day cycle; Biological: Autologous Stem Cell Transplant (ASCT); Participants who are MRD positive at the conclusion of 8 cycles of study treatment, and were able to have their stem cells that were extracted, will receive ASCT from participants' bone marrow samples.
Experimental: Arm C- Carfilzomib, Lenalidomide and Dexamethasone with Daratumumab (DKrd); Participants in this group will receive Carfilzomib, Lenalidomide, Dexamethasone with Daratumumab, Acetaminophen, Diphenhydramine and Montelukast on a 28 day cycle. Participants achieving a PR or better at the end of 4 cycles will continue to receive a total of 8 cycles of combination therapy. Participants with less than PR after completing 4 cycles will go off study therapy. After 8 cycles of therapy, participants who are MRD positive will have the option to receive an ASCT if stem cells were able to be extracted, before initiating maintenance therapy with Lenalidomide for up to 2 years, and patients who are MRD negative will go directly on to receive maintenance therapy with Lenalidomide for up to 2 years.	Drug: Dexamethasone; 20 mg or 40 mg per dose administered by mouth (PO) or IV. Participants randomized in Arm A: 20 mg/dose on days 1, 4, 8 and 11 on a 21 day treatment cycle; Participants randomized in Arm B: Cycles 1 through 4 - 40mg/dose on days 1, 8 and 15 on a 28 day cycle; Cycles 5 through 8 - 20mg/dose on days 1, 8, 15 on a 28 day cycle Participants randomized in Arm C: Cycle 1 - 20 mg/dose on days 1, 2, and 22, and 40mg/dose on days 8 and 15 on a 28 day cycle; Cycle 2 - 40 mg/dose on days 1, 8, and 15 and 20mg/dose o day 22 on a 28 day cycle; Cycles 3-4 - 40mg/dose on Days 1, 8, 15 on a 28 day cycle; Cycles 5-8 - 20mg/dose on days 1, 8, 15 on a 28 day cycle; Drug: Lenalidomide; 10 or 25 mg/day capsules administered PO. Participants randomized in Arm A: 25 mg/day capsules on Days 1 through 14 of a 21 day cycle.; Participants randomized in Arm B: Cycles 1 through 8 - 25 mg/day capsules on Days 1 through 21 of a 28 day cycle; Participants randomized in Arm C: Cycles 1 - 25 mg/day capsules on Days 2 through 21 of a 28 day cycle; Cycles 2 through 8 - 25 mg/day capsules on Days 1 through 21 of a 28 day cycle; Maintenance Therapy: 10 mg capsules on Days 1 through 21 on a 28 days cycle.; Other Name: Revlimid; Drug: Acetaminophen; 650 mg administered PO. Participants randomized to Arm C: Cycles 1 through 8 - 650 mg administered on Days 1, 8 and 15.; Drug: Diphenhydramine; 25 mg administered via IV Participants randomized to Arm C: Cycles 1 through 8 - 25 mg administered on Days 1, 8 and 15.; Drug: Montelukast; 10 mg administered PO to participants randomized to Arm C prior to the first 4 doses of Daratumumab.; Drug: Carfilzomib; 20 mg or 56 mg/m2 per dose administered via IV. Participants randomized to Arm B: Cycle 1 - 20 mg/m2 per dose on Day 1 and 56 mg/m2 per dose on days 8 and 15 of a 28 day cycle; Cycles 2 through 8 - 56 mg/m2 per dose on days 1, 8 and 15 of a 28 day cycle; Participants randomized to Arm C: Cycle 1 - 20 mg/m2 per dose on Day 2 and 56 mg/m2 per dose on days 8 and 15 of a 28 day cycle; Cycles 2 through 8 - 56 mg/m2 per dose on days 1, 8 and 15 of a 28 day cycle; Drug: Daratumumab; 16 mg/kg administered via IV or 1800 mg SC, per treating physician discretion. Participants randomized to Arm C: Cycles 1 though 2 - 16 mg/kg IV or 1800 mg SC on days 1, 8, 15, and 22 of a 28 day cycle; Cycles 3 through 6- 16 mg/kg IV or 1800 mg SC on days 1 and 15 of a 28 day cycle; Cycles 7 through 8 - 16 mg/kg IV or 1800 mg SC on day 1 of a 28 day cycle; Biological: Autologous Stem Cell Transplant (ASCT); Participants who are MRD positive at the conclusion of 8 cycles of study treatment, and were able to have their stem cells that were extracted, will receive ASCT from participants' bone marrow samples.

Outcome Measures

Primary Outcome Measures :

1. Rate of Minimal Residual Disease (MRD) Negativity [ Time Frame: Up to 32 weeks ]
   MRD will be assessed from bone marrow samples.

Secondary Outcome Measures :

1. Overall Survival [ Time Frame: Up to 16 weeks ]
   Overall survival is defined as the time from date of randomization to death from any cause
2. Progression Free Survival (PFS) [ Time Frame: Up to 16 weeks ]
   PFS is defined as time from date of randomization to time of progression or death, whichever occurs first.
3. Event Free Survival (EFS) [ Time Frame: Up to 16 weeks ]
   EFS is defined as time from date of randomization to the time of 1) achieving a PR or less with the first four cycles of therapy, 2) transplant, 3) progression, or 4) death, whichever occurs first.
4. Rate of Response [ Time Frame: Up to 3 years ]
   Rate of Response will be reported as the percentage of participants achieving a response of: a) Partial Response (PR) or better, b) Very Good Partial Response (VGPR) or better and c) Complete Response (CR) and Stringent Complete Response (sCR). Responses will be evaluated from participant serum, urine and bone marrow samples.
5. Rate of MRD Negativity as best response [ Time Frame: Up to 3 years ]
   MRD will be evaluated from bone marrow samples.
6. Incidence of treatment related toxicity [ Time Frame: Up to 9 months ]
   Toxicity will be evaluated by treating physician using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.
7. Minimal Residual Disease (MRD) Negativity [ Time Frame: Up to 3 years ]
   MRD Negativity using bone marrow and blood samples

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Newly diagnosed patients with histologically confirmed Multiple Myeloma (MM) based on the following criteria:

• Clonal plasma cells in the bone marrow

• Measurable disease within the past 4 weeks defined by any one of the following:

  • Serum monoclonal protein >/= 1.0 g/dL
  • Urine monoclonal protein >/= 200 mg/24 hour
  • Involved serum immunoglobulin free light chain >/= 10 mg/dL and abnormal kappa/lambda ratio 2. Evidence of underlying end organ damage and/or myeloma defining event attributed to underlying plasma cell proliferative disorder meeting at least one of the following:
• Hypercalcemia: serum calcium > 0.25 millimoles (mmol) /L (> 1 mg/dL) above upper limit of normal or >/= 2.75 mmol (11 mg/dL)
• Anemia: hemoglobin value <10 g/dL or >2 g/dL below lower limit of normal
• Bone disease >/= 1 lytic lesions on skeletal X-ray, CT, or Positron Emission Tomography (PET)-CT. For patients with 1 lytic lesion, bone marrow should demonstrate >/=10% clonal plasma cells
• Clonal bone marrow plasma cell percentage >/=60%
• Involved/un-involved serum free light chain ratio >/=100 and involved free light chain >/=100 mg/L
• > 1 focal lesion on magnetic resonance imaging study (lesion must be >5mm) in size

• For patients with 1 lytic lesion, bone marrow should demonstrate ≥10% clonal plasma cells 3. Creatinine clearance (CrCl) >/=60 ml/min. CrCl can be measured or estimated using Cockcroft-Gault method, Modification of Diet in Renal Disease (MDRD), or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulae 4. Age >/= 18 years at the time of signing the informed consent documentation. Age limit of </= 75 years 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 6. Absolute neutrophil count (ANC) >/= 1.0 K/microliter (uL), hemoglobin >/= 8 g/dL, and platelet count >/= 75 K/uL, unless if cytopenias are deemed to be due disease at discretion of clinical investigator. Transfusions and growth factors are permissible.

  7. Adequate hepatic function, with bilirubin < 1.5 x the Upper Limit of Normal (ULN), and Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) < 3.0 x ULN 8. All study participants must be able to tolerate one of the following thromboprophylactic strategies: aspirin, low molecular weight heparin or warfarin (Coumadin) or alternative anti-coagulant 9. All study participants must be registered into the mandatory electronic REMS (eREMS) program and be willing and able to comply with the requirements of Risk Evaluation Management and Safety (REMS).

  10) Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 10-14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control, one highly effective method and one additional effective method at the same time, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy.

• A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Exclusion Criteria:

1. Patients receiving >1 cycle of prior treatment or concurrent systemic treatment for multiple myeloma:

   • Treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with current or prior corticosteroids is permitted
   • Bone targeting agents are permitted
   • Concurrent or prior treatment with corticosteroids for indications other than multiple myeloma is permitted
   • Prior treatment with radiotherapy is permitted
   • Prior MM treatment, such as Immunomodulating Drugs (IMIDs) or nonn-MM drugs in clinical trials for smoldering myeloma is permitted with a washout period of 2 weeks from last dose. Smoldering patients previously treated carfilzomib are excluded
   • Patients with measurable disease who received up to one cycle of any therapy within 60 days with a washout period of 2 weeks from last dose (on a trial or outside a trial) are eligible (Note: Measurable disease is defined as one or more of the following: Serum monoclonal protein ≥ 1.0 g/dL, Urine monoclonal protein ≥ 200 mg/24 hour and/ or Involved serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal kappa/lambda ratio)
2. Plasma cell leukemia
3. Polyneuropathy, Organomegaly, Endocrinopathy, Myeloma protein, and Skin changes (POEMS) syndrome
4. Amyloidosis
5. Has known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal (note that FEV1 testing is required for subjects suspected of having chronic obstructive pulmonary disease and subjects must be excluded if FEV1 <50% of predicted normal).
6. Pregnant or lactating females. Because there is a potential risk for adverse events nursing infants secondary to treatment of the mother with carfilzomib in combination with lenalidomide. These potential risks may also apply to other agents used in this study.
7. Uncontrolled hypertension (i.e. systolic BP >160 mmHg, diastolic BP > 100 mmHg) or or diabetes
8. Active hepatitis B or C infection

9. Subject is:

   • Seropositive for human immunodeficiency virus (HIV)
   • Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen (anti-HBc) and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. Exception: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by Polymerase Chain Reaction (PCR).
   • Seropositive for hepatitis C (except in the setting of a sustained virologic response (SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy).
10. Significant cardiovascular disease with New York Heart Association (NYHA) class III or IV symptoms, symptomatic ischemia, current uncontrolled arrhythmias, screening ECG with corrected QT interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction within 4 months prior to randomization and Left ventricular ejection fraction < 40% assessed by transthoracic echocardiogram (ECHO),Current unstable angina as determined by history and physical exam, hypertrophic cardiomyopathy or restrictive cardiomyopathy
11. Pulmonary hypertension
12. Has refractory Gastrointestinal (GI) disease with refractory nausea/vomiting, inflammatory bowel disease, or bowel resection that would prevent absorption of oral agents
13. Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance with study requirements
14. Significant neuropathy >/= Grade 3 or Grade 2 neuropathy with pain at baseline
15. Contraindication to any concomitant medication, including antivirals or anticoagulation.
16. Major surgery within 3 weeks prior to first dose

Contacts and Locations

Contacts

Contact: Philip Arlen; 305-243-5247; paa107@miami.edu

Locations

United States, Florida

University of Miami; Recruiting

Miami, Florida, United States, 33136

Contact: Philip Arlen, MD 305-243-5247 paa107@miami.edu

Principal Investigator: Carl Landgren, MD

Moffitt Cancer Center; Not yet recruiting

Tampa, Florida, United States, 33612-9497

Contact: Ken Shain, MD 888-663-3488 Ken.Shain@moffitt.org

Principal Investigator: Ken Shain, MD

United States, Illinois

Rush University Medical Center; Not yet recruiting

Chicago, Illinois, United States, 606012

Contact: Agne Paner, MD 888-352-7874 Agne_Paner@rush.edu

Principal Investigator: Agne Paner, MD

United States, New York

Roswell Park Comprehensive Cancer Center; Not yet recruiting

Buffalo, New York, United States, 14203

Contact: Ariffa Kariapper 716-845-3838 Ariffa.Kariapper@RoswellPark.org

Principal Investigator: Jens Hillengass, MD

Memorial Sloan Kettering Cancer Center; Suspended

New York, New York, United States, 10065

Stony Brook University; Not yet recruiting

Stony Brook, New York, United States, 11794

Contact: Aisha Hashmi 631-638-0836 Aisha.Hashmi@stonybrookmedicine.edu

Principal Investigator: Huda Salman, MD, PhD

United States, Texas

MD Anderson Cancer Center; Not yet recruiting

Houston, Texas, United States, 77030

Contact: Elisabet Manasanch, MD 713-745-8092 EEManasanch@mdanderson.org

Principal Investigator: Elisabet Manasanch, MD

United States, Utah

Huntsman Cancer Institue; Not yet recruiting

Salt Lake City, Utah, United States, 84113

Contact: Douglas Sborov, MD 801-585-2626 Douglas.Sborov@hsc.utah.edu

Principal Investigator: Douglas Sborov, MD

Sweden

Skåne University Hospital; Not yet recruiting

Malmö, Sweden, 9, 214

Contact: Markus Hannson, MD +46 40 33 10 00 markus.hansson@med.lu.se

Principal Investigator: Markus Hannson, MD

Sponsors and Collaborators

University of Miami

Amgen

Investigators

• Principal Investigator: Carl Landgren, MD; University of Miami

More Information

• Responsible Party: University of Miami
• ClinicalTrials.gov Identifier: NCT04268498
• Other Study ID Numbers: 20201316
• First Posted: February 13, 2020
• Last Update Posted: June 11, 2021
• Last Verified: June 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by University of Miami:

Daratumumab; Carfilzomib; Lenalidomide

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Acetaminophen; Diphenhydramine; Promethazine; Dexamethasone; Lenalidomide; Bortezomib; Daratumumab; Montelukast; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones