Myeloma-Developing Regimens Using Genomics (MyDRUG)

Sponsor

Multiple Myeloma Research Consortium (Other)

Overall Status

Recruiting

CT.gov ID

NCT03732703

Collaborator

AbbVie (Industry), Celgene Corporation (Industry), Eli Lilly and Company (Industry), Genentech, Inc. (Industry), Janssen, LP (Industry), Takeda (Industry), GlaxoSmithKline (Industry), Karyopharm Therapeutics Inc (Industry)

228

Enrollment

Locations

Arms

58.3

Anticipated Duration (Months)

13.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The MyDRUG study is a type of Precision Medicine trial to treat patients with drugs targeted to affect specific genes that are mutated as part of the disease. Mutations in genes can lead to uncontrolled cell growth and cancer. Patients with a greater than 25% mutation to any of the following genes; CDKN2C, FGFR3, KRAS, NRAS, BRAF V600E, IDH2 or T(11;14) can be enrolled to one of the treatment arms. These arms have treatments specifically directed to the mutated genes. Patients that do not have a greater than 25% mutation to the genes listed can be enrolled to a non-actionable treatment arm.

The genetic sequencing of the patient's tumor is required via enrollment to the MMRF002 study: Clinical-grade Molecular Profiling of Patients with Multiple Myeloma and Related Plasma Cell Malignancies. (NCT02884102).

Condition or Disease	Intervention/Treatment	Phase
Relapsed Refractory Multiple Myeloma	Drug: Abemaciclib, dexamethasone, ixazomib, pomalidomide Drug: Enasidenib, dexamethasone, ixazomib, pomalidomide Drug: Cobimetinib, dexamethasone, ixazomib, pomalidomide Drug: Erdafitinib, dexamethasone, ixazomib, pomalidomide Drug: Venetoclax, dexamethasone, ixazomib, pomalidomide Drug: Daratumumab, dexamethasone, ixazomib, pomalidomide Drug: Belantamab mafodotin, dexamethasone, ixazomib, pomalidomide Drug: Selinexor, dexamethasone, ixazomib, pomalidomide	Phase 1/Phase 2

Detailed Description

The study will enroll 228 patients enrolled to one of eight treatment arms. The study is open to patients relapsing with relapsed refractory multiple myeloma, who have

received at least one prior but no more than 3 prior therapies
exposed to both a PI and an IMiD
had early relapse after initial treatment. Relapse is defined as the IMWG uniform response criteria (Kumar et al, 2016). Early relapse as defined by at least one of the following:

Relapse within 3 years post autologous stem cell transplantation (ASCT) on maintenance, or 18 months if unmaintained
Relapse within 18 months of initial non-ASCT based therapy

Study Design

Study Type:

Interventional

Anticipated Enrollment :

228 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Eight Arms with 38 patients per armEight Arms with 38 patients per arm

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Myeloma-Developing Regimens Using Genomics (MyDRUG) (Genomics Guided Multi-arm Trial of Targeted Agents Alone or in Combination With a Backbone Regimen)

Actual Study Start Date :

Apr 1, 2019

Anticipated Primary Completion Date :

Feb 10, 2022

Anticipated Study Completion Date :

Feb 10, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sub-Protocol A1 Patients with CDK activating alteration receive Abemaciclib in combination with ixazomib, pomalidomide and dexamethasone (IPd)	Drug: Abemaciclib, dexamethasone, ixazomib, pomalidomide Patients with relapsed Multiple Myeloma will receive Abemaciclib and Dexamethasone for the first 2 cycles. Abemaciclib, Dexamethasone, Ixazomib and Pomalidomide from cycle 3 forward. Each cycle is 28 days long. Other Names: abemaciclib: Verzenio, LY2835219 ixazomib: Ninlaro, MLN2238 pomalidomide: Pomalyst
Experimental: Sub-Protocol B1 Patients with IDH2 activating mutation receive Enasidenib in combination with ixazomib, pomalidomide and dexamethasone (IPd)	Drug: Enasidenib, dexamethasone, ixazomib, pomalidomide Patients with relapsed Multiple Myeloma will receive Enasidenib and Dexamethasone for the first 2 cycles. Enasidenib, Dexamethasone, Ixazomib and Pomalidomide from cycle 3 forward. Each cycle is 28 days long. Other Names: enasidenib: AG221, IDHIFA ixazomib: Ninlaro, MLN2238 pomalidomide: Pomalyst
Experimental: Sub-Protocol C1 Patients with the presence of RAF/RAS mutation receive Cobimetinib in combination with ixazomib, pomalidomide and dexamethasone (IPd)	Drug: Cobimetinib, dexamethasone, ixazomib, pomalidomide Patients with relapsed Multiple Myeloma will receive Cobimetinib and Dexamethasone for the first 2 cycles. Cobimetinib, Dexamethasone, Ixazomib and Pomalidomide from cycle 3 forward. Each cycle is 28 days long. Other Names: cobimetinib: Cotellic, GDC-0973, RG7420 ixazomib: Ninlaro, MLN2238 pomalidomide: Pomalyst
Experimental: Sub-Protocol D1 Patients with presence of FGFR3 activating mutations receive Erdafitinib in combination with ixazomib, pomalidomide and dexamethasone (IPd)	Drug: Erdafitinib, dexamethasone, ixazomib, pomalidomide Patients with relapsed Multiple Myeloma will receive Erdafitinib and Dexamethasone for the first 2 cycles. Erdafitinib, Dexamethasone, Ixazomib and Pomalidomide from cycle 3 forward. Each cycle is 28 days long. Other Names: erdafitinib: G-024, JNJ-42756493, JNJ-493 ixazomib: Ninlaro, MLN2238 pomalidomide: Pomalyst
Experimental: Sub-Protocol E1 Patients with t(11;14) translocation will be enrolled in arm E1 and randomized to the venetoclax or the IPd control arm. Patients with relapsed Multiple Myeloma will receive Venetoclax, Ixazomib, Pomalidomide and Dexamethasone every cycle. Each cycle is 28 days long.	Drug: Venetoclax, dexamethasone, ixazomib, pomalidomide Patients with t(11;14) translocation will be enrolled in arm E1 and randomized to the venetoclax or the IPd control arm. Patients with relapsed Multiple Myeloma will receive Venetoclax, Ixazomib, Pomalidomide and Dexamethasone every cycle. Each cycle is 28 days long. Other Names: venetoclax: Venclexta: ABT-199 ixazomib: Ninlaro, MLN2238 pomalidomide: Pomalyst
Experimental: Sub-Protocol Y1 Patients with Non-Actionable Genetic Abnormality receive Daratumumab in combination with ixazomib, pomalidomide and dexamethasone (IPd)	Drug: Daratumumab, dexamethasone, ixazomib, pomalidomide Patients with relapsed Multiple Myeloma will receive Daratumumab, Ixazomib, Pomalidomide and Dexamethasone every cycle. Each cycle is 28 days long. Other Names: daratumumab: Darzalex ixazomib: Ninlaro, MLN2238 pomalidomide: Pomalyst
Experimental: Sub-Protocol Y2 Patients with Non-Actionable Genetic Abnormality receive Belantamab mafodotin in combination with ixazomib, pomalidomide and dexamethasone (IPd)	Drug: Belantamab mafodotin, dexamethasone, ixazomib, pomalidomide Patients with relapsed Multiple Myeloma will receive Belantamab mafodotin, Ixazomib, Pomalidomide and Dexamethasone every cycle. Each cycle is 28 days long. Other Names: Belantamab mafodotin: BLENREP, GSK2857916
Experimental: Sub-Protocol Y3 Patients with Non-Actionable Genetic Abnormality receive Selinexor in combination with ixazomib, pomalidomide and dexamethasone (IPd)	Drug: Selinexor, dexamethasone, ixazomib, pomalidomide Patients with relapsed Multiple Myeloma will receive Selinexor, Ixazomib, Pomalidomide and Dexamethasone every cycle. Each cycle is 28 days long. Other Names: Selinexor: XPOVIO

Outcome Measures

Primary Outcome Measures

Overall Response Rate - Actionable Genetic Alteration [Patients will be evaluated monthly for response from the start of the study until the date of documented disease progression, assessed up to 2 years]
• To evaluate the overall response rate (ORR) with targeted agents used in combination with backbone regimen ixazomib, pomalidomide and dexamethasone (IPd) in patients with an actionable genetic alteration per the International Myeloma Working Group [IMWG] consensus criteria (Kumar et al, 2016)
Overall Response Rate - Non-Actionable Genetic Alteration [Patients will be evaluated monthly for response from the start of the study until the date of documented disease progression, assessed up to 2 years]
• To evaluate the ORR with agents used in combination with backbone (or IPd) regimen in patients with no actionable genetic alteration per IMWG consensus criteria (Kumar et al, 2016).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Willing to be registered into the pomalidomide (POMALYST®) Risk Evaluation and Mitigation Strategy (REMS®) program
Enrolled in the MMRF002 Molecular Profiling Protocol (NCT02884102) with report less than 120 days old
Disease free of prior malignancies for ≥ 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or prostate cancer not requiring therapy
High risk patients with relapsed refractory multiple myeloma (RRMM), who have:
received at least one prior but no more than 3 prior therapies
exposed to both a PI and an IMiD
had early relapse after initial treatment Early relapse as defined by at least one of the following: (Relapse is defined as the IMWG uniform response)

Relapse within 3 years of initiation of induction chemo therapy for post autologous stem cell transplantation (ASCT) followed by maintenance, or 18 months if unmaintained after ASCT
Within 18 months of initial non-ASCT based therapy

Patients must have progressed after their most recent treatment and require therapy for myeloma
Females of reproductive potential must have a negative pregnancy test at baseline, be non-lactating, and willing to adhere to scheduled pregnancy testing
Females of reproductive potential and males must practice and acceptable method of birth control
Laboratory values obtained ≤ 14 days prior to registration:
Absolute neutrophil count (ANC) ≥ 1000/ul
Hemoglobin (Hgb) ≥ 8 g/dl
Platelet (PLT) ≥ 75,000/ul
Total bilirubin <1.5 x upper limit of normal (ULN) or if total bilirubin is >1.5 x ULN, the direct bilirubin must be ≤ 2.0 mg/dL
Aspartate aminotransferase (AST) <3 x ULN
Creatinine Clearance ≥ 30 mL/min

Measurable disease of Multiple Myeloma (MM) as defined by at least one of the following:

Serum monoclonal protein ≥ 0.5 g by protein electrophoresis
≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis
Serum immunoglobulin free light chain (FLC) ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda FLC ratio
Monoclonal bone marrow plasmacytosis ≥30% (evaluable disease)
Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, or 2
Ability to take aspirin, warfarin, or low molecular weight heparin

Sub-Protocol Inclusion Criteria:

Refer to each respective Sub Protocol for additional inclusion criteria.

Exclusion Criteria:

Patients will be ineligible for this study if they meet any one of the following criteria:

Aggressive multiple myeloma requiring immediate treatment as defined by:
Lactate dehydrogenase (LDH) > 2 times ULN
Presence of symptomatic extramedullary disease or central nervous system involvement
Hypercalcemia >11.5 mg/dl
Acute worsening of renal function (CrCl < 30 ml/min) directly related to myeloma relapse
Any neurological emergency related to myeloma
Clinical symptoms of hyperviscosity related to monoclonal protein
Involved serum free light chain > 100 mg/dL (1000 mg/L) in the setting of prior diagnosis of cast nephropathy
Infection requiring systemic antibiotic therapy or other serious infection within 14 days of enrolment
Known hypersensitivity or development of erythema nodosum if characterized by a desquamating rash while taking thalidomide, lenalidomide, pomalidomide or similar drug. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of the agents
Prior Ixazomib/Pomalidomide/Dexamethasone combination therapy
Pregnant or breast-feeding females
Serious medical or psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance, interfere in the completion of treatment per protocol, or follow-up evaluation
Active hepatitis A, B or C viral infection or known human immunodeficiency virus (HIV) infection
Concurrent symptomatic amyloidosis or plasma cell leukemia
POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes]
Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (Alopecia any grade and/or neuropathy Grade 2 without pain are permitted)
Prior allogeneic or ASCT within 12 weeks of initiation of therapy. Prior allogeneic stem cell transplant with active graft-versus-host disease (GVHD)
Prior experimental therapy within 14 days of protocol treatment or 5 half-lives of the investigational drug, whichever is longer
Prior anticancer therapy within 14 days of initiation of protocol therapy (Dexamethasone/ 40mg/day) for a maximum of 4 days before screening is allowed
Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy).
Known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or Gastro Intestinal (GI) absorption of drugs administered orally
Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months
Other co-morbidity, which would interfere with patient's ability to participate in trial or that confounds the ability to interpret data from the study

Sub-Protocol Exclusion Criteria:

Refer to each respective Sub Protocol for additional exclusion criteria.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic - Arizona	Phoenix	Arizona	United States	85054
2	City of Hope	Duarte	California	United States	91010
3	Emory University	Atlanta	Georgia	United States	30322
4	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
5	Beth Israel Deaconess	Boston	Massachusetts	United States	02215
6	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
7	University of Michigan Health System	Ann Arbor	Michigan	United States	48109
8	Karmanos Cancer Center	Detroit	Michigan	United States	48201
9	Mayo Clinic - Minnesota	Rochester	Minnesota	United States	55905
10	Washington University School of Medicine Division of Medical Oncology	Saint Louis	Missouri	United States	63110
11	Hackensack University Medical Center	Hackensack	New Jersey	United States	07610
12	Mount Sinai School of Medicine	New York	New York	United States	10029
13	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
14	Levine Cancer Institute	Charlotte	North Carolina	United States	28204
15	Ohio State University College of Medicine	Columbus	Ohio	United States	43210
16	UT Southwestern Medical Center	Dallas	Texas	United States	75390
17	Virginia Cancer Specialists	Fairfax	Virginia	United States	22031

Investigators

Principal Investigator: Hearn J Cho, M.D., Ph.D., Multiple Myeloma Research Consortium
Principal Investigator: Daniel Auclair, Ph.D., Multiple Myeloma Research Consortium