Study of Bendamustine and IXAZOMIB (MLN9708) Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma

NCT02477215 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: PRO00024991
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

This Phase I/II study is designed to first identify doses of MLN9708 and bendamustine that are associated with an acceptable adverse event profile when delivered together in 28-day cycles. Additionally, the study aims to assess the efficacy of the combination in patients with relapsed/refractory multiple myeloma. Responders (stable disease or more), will continue to receive up to eight cycles total in the absence of further progressive disease.

Conditions

Multiple Myeloma

Keywords

Multiple Myeloma

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose of Bendamustine

  Maximum tolerated dose of bendamustine in combination with fixed doses of ixazomib (MLN9708) and dexamethasone will be determined from the incidence of dose limiting toxicities at each dosage.

  Six months for each dosing cohort

• Objective Response Rate

  Objective response rate was defined as the number of subjects achieving a complete response (CR) or partial response (PR) after at least four cycles of ixazomib (MLN9708) and bendamustine plus dexamethasone.

  18 months

Secondary Outcomes (5)

• Overall Survival (OS)

  36 months

• Progression Free Survival (PFS)

  18 months

• Cumulative Response Rates in Patients After Eight Cycles.

  18 months

• Duration of Response (DoR)

  36 months

• Number of Participants Experiencing Dose-Limiting Toxicity (DLT)

  Six months

Study Arms (2)

MLN9708, Bendamustine and Dexamethasone Dose Escalation

EXPERIMENTAL

Ixazomib 4 mg, days 1, 8, 15. Dexamethasone 40 mg oral weekly. Bendamustine dose levels: 70 mg/m\^2, 80mg/m\^2, or 90 mg/m\^2 given on days 1 and 2

Drug: MLN9708; Drug: Dexamethasone; Drug: Bendamustine (multiple dose levels)

MLN9708, Bendamustine and Dexamethasone MTD

EXPERIMENTAL

Ixazomib 4 mg, days 1, 8, 15. Dexamethasone 40 mg oral weekly. Bendamustine dose levels: MTD given on days 1 and 2

Drug: MLN9708; Drug: Dexamethasone; Drug: Bendamustine (MTD)

Interventions

MLN9708 DRUG

4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.

Also known as: Ixazomib

MLN9708, Bendamustine and Dexamethasone Dose Escalation; MLN9708, Bendamustine and Dexamethasone MTD

Dexamethasone DRUG

40 mg oral on Days 1, 8, 15 of each 28 day cycle.

Also known as: Decadron

MLN9708, Bendamustine and Dexamethasone Dose Escalation; MLN9708, Bendamustine and Dexamethasone MTD

Bendamustine (multiple dose levels) DRUG

70 mg/m\^2, 80 mg/m\^2, or 90 mg/m\^2 on days 1 and 2

Also known as: Treanda, Treakisym, Ribomustin

MLN9708, Bendamustine and Dexamethasone Dose Escalation

Bendamustine (MTD) DRUG

80 mg/m\^2 on days 1 and 2

Also known as: Treanda, Treakisym, Ribomustin

MLN9708, Bendamustine and Dexamethasone MTD

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients 18 years or older.
• Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
• Female patients who:
• Are postmenopausal for at least one year before the screening visit, OR
• Are surgically sterile, OR
• If they are of childbearing potential, agree to practice two effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.)
• Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following:
• Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.)
• Patients must have have histologically or cytologically confirmed symptomatic Multiple Myeloma, who are non-responsive to or ineligible for autologous stem cell transplant, and who progress after prior exposure to proteasome inhibitor (bortezomib, carfilzomib) and lenalidomide or pomalidomide or thalidomide (IMID); and refractory/progressing to at least one of these agents and must meet at least one of the following parameters of measurable disease:
• Measurable levels of monoclonal protein (M protein): \> 1 g/dL of immunoglobin G (IgG) or immunoglobin M (IgM) M-protein or \> 0.5 g/dL immunoglobin A (IgA) or immunoglobin D (IgD) M protein on serum protein electrophoresis OR \> 200 mg/24h of free light chain proteinuria on a 24 hour urine protein electrophoresis which must be obtained within 4 weeks prior to registration OR \> 10 mg/dL involved free light chain on serum free light chain testing with an abnormal kappa:lambda light chain ratio.
• Patients with lytic bone disease, defined as at least one lytic lesion that can be accurately measured in at least one dimension.
• Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2.
• Patients are eligible after autologous or allogeneic stem cell transplantation. Allogeneic transplantation can be enrolled only if they have no ongoing transplant related side effects.
• Patients must be at least 2 weeks from major surgery, radiation therapy, participation in other investigational trials and have recovered from clinically significant toxicities of these prior treatments

You may not qualify if:

• Female patients who are lactating or have a positive serum pregnancy test during the screening period.
• Major surgery within 14 days before enrollment.
• Central nervous system involvement.
• Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
• 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.
• Systemic treatment, within 14 days before the first dose of IXAZOMIB, with strong inhibitors of cytochrome P1A2 (CYP1A2) (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P3A (CYP3A) (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.
• Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of IXAZOMIB including difficulty swallowing.
• Diagnosed or treated for another malignancy where the expected survival is less than two years will be excluded. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• Patient has ≥ Grade 2 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.
• Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.
• Patients that have previously been treated with IXAZOMIB, or participated in a study with IXAZOMIB whether treated with IXAZOMIB or not.
• Patients with a history of severe chronic obstructive pulmonary disease requiring ongoing oxygen support or those with a resting oxygen saturation \<92% on room air irrespective of the cause.

Sponsors & Collaborators

• Parameswaran Hari: lead

Study Sites (1)

Froedtert Hospital and the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

ixazomib; Dexamethasone; Calcium Dobesilate; Bendamustine Hydrochloride; Maximum Tolerated Dose

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Butyrates; Acids, Acyclic; Carboxylic Acids; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Toxicity Tests; Investigative Techniques; Toxicological Phenomena; Pharmacological and Toxicological Phenomena; Physiological Phenomena

Results Point of Contact

• Title: Parameswaran Hari
• Organization: Medical College of Wisconsin

phari@mcw.edu

414-805-4600

Study Officials

• Parameswaran Hari, MD, MRCP, MS

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Section Head, Hematological Malignancies Director, Adult Blood and Marrow Transplant Program

Study Record Dates

• First Submitted: June 12, 2015
• First Posted: June 22, 2015
• Study Start: October 9, 2015
• Primary Completion: May 2, 2018
• Study Completion: September 17, 2020
• Last Updated: October 22, 2020
• Results First Posted: January 27, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)