Clinical trial NCT03732703: Myeloma-Developing Regimens Using Genomics (MyDRUG)
Official title: Myeloma-Developing Regimens Using Genomics (MyDRUG) (Genomics Guided Multi-arm Trial of Targeted Agents Alone or in Combination With a Backbone Regimen)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Relapsed Refractory Multiple Myeloma
Keywords: Multiple Myeloma
Relapsed Refractory
Multiple Myeloma Research Consortium (MMRC)
Genomic Profile
My Drug
Multiple Myeloma Research Foundation
Lead sponsor: Multiple Myeloma Research Consortium
Sponsor class: NETWORK
Collaborators: name: AbbVie
name: Celgene Corporation
name: Eli Lilly and Company
name: Genentech, Inc.
name: Janssen, LP
name: Takeda
name: GlaxoSmithKline
name: Karyopharm Therapeutics Inc
First posted: 2018-11-07
Enrollment: 103
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Eight Arms with 38 patients per arm
Primary purpose: TREATMENT

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).

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:

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

Eligibility criteria: 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)

    1. 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
    2. 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.

Primary outcomes:
measure: Overall Response Rate - Actionable Genetic Alteration
timeFrame: 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
measure: Overall Response Rate - Non-Actionable Genetic Alteration
timeFrame: 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
Secondary outcomes:
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic - Arizona
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine Division of Medical Oncology
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University College of Medicine
state: Ohio
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
Study officials:
affiliation: Multiple Myeloma Research Consortium
name: Hearn J Cho, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, Munshi N, Lonial S, Blade J, Mateos MV, Dimopoulos M, Kastritis E, Boccadoro M, Orlowski R, Goldschmidt H, Spencer A, Hou J, Chng WJ, Usmani SZ, Zamagni E, Shimizu K, Jagannath S, Johnsen HE, Terpos E, Reiman A, Kyle RA, Sonneveld P, Richardson PG, McCarthy P, Ludwig H, Chen W, Cavo M, Harousseau JL, Lentzsch S, Hillengass J, Palumbo A, Orfao A, Rajkumar SV, Miguel JS, Avet-Loiseau H. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016 Aug;17(8):e328-e346. doi: 10.1016/S1470-2045(16)30206-6.