Ixazomib as a Replacement for Carfilzomib and Bortezomib for Multiple Myeloma Patients

NCT02206425 | Completed Phase 1 DMC

• 2 other identifiers: X16041IISR-2013-M100118
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 12

Brief Summary

The goal of this clinical research study is to evaluate the safety and effectiveness (good and bad effects) of ixazomib given as part of a combination therapy to treat subjects with relapsed (subjects whose disease came back) or refractory (subjects whose disease did not respond to past treatment) multiple myeloma. More specifically, the study is focused on subjects who were previously treated with bortezomib (Velcade®) or carfilzomib (Kyprolis®) and showed worsening of their myeloma while receiving either one of these drugs in combination therapy. This study is a Phase I/II. Ixazomib is an investigational drug, which means that ixazomib is currently being tested and is not yet approved by the United States Food and Drug Administration (FDA) for subjects with relapsed or refractory multiple myeloma. Ixazomib is a new study drug that belongs to the same class as bortezomib and carfilzomib; however, unlike bortezomib and carfilzomib, ixazomib is taken by mouth. Current studies investigating ixazomib are demonstrating that it is as safe as bortezomib and effective for the treatment of multiple myeloma both on its own and in combination with other multiple myeloma medications, such as lenalidomide and dexamethasone, or prednisone and melphalan.

Conditions

Multiple Myeloma

Keywords

multiple myeloma; Relapsed/refractory; Ixazomib; Proteasome inhibitor; Oral

Outcome Measures

Primary Outcomes (4)

• Maximum tolerated dose (MTD) for selected regimens

  MTD determined via the number of dose-limiting toxicities (DLTs) per cohort for the following ixazomib- containing combinations: bortezomib+ cyclophosphamide + dexamethasone, bortezomib + cyclophosphamide + ascorbic acid, bortezomib + PLD + dexamethasone

  Cycles 1-2 for selected regimens (up to 2 months)

• Number of subjects with adverse events

  Occurrence of adverse events throughout the study, graded via CTCAE v 4.03 criteria

  up to 48 months

• Overall response rate (ORR)

  Complete response (CR)+ very good partial response (VGPR) + partial response (PR), defined using IMWG criteria

  up to 48 months

• Clinical benefit rate (CBR)

  CBR=ORR + minor response (MR)

  up to 48 months

Secondary Outcomes (6)

• Time to Progression

  at least over 48 months

• Progression-free survival (PFS)

  at least over 48 months

• Time to response (TTR)

  up to 48 months

• Duration of response (DOR)

  at least over 48 months

• Overall survival (OS)

  at least over 48 months

Study Arms (10)

bortezomib + melphalan + prednisone

EXPERIMENTAL

Ixazomib will be administered PO at 4 mg on Days 1, 8 and 15 of a 28-day cycle. All other agents will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed. Patients that were on a 21-day cycle schedule will follow a 28-day cycle schedule and receive ixazomib on days 1, 8 and 15. Other drugs will be administered on the same days as they were given on their prior 21-day cycle schedule, except that, in the new 28-day schedule, day 1 of other drugs will be the same as day 1 of ixazomib.

Drug: Melphalan; Drug: Prednisone

bortezomib + dexamethasone

EXPERIMENTAL

Ixazomib will be administered PO at 4 mg on Days 1, 8 and 15 of a 28-day cycle. All other agents will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed. Patients that were on a 21-day cycle schedule will follow a 28-day cycle schedule and receive ixazomib on days 1, 8 and 15. Other drugs will be administered on the same days as they were given on their prior 21-day cycle schedule, except that, in the new 28-day schedule, day 1 of other drugs will be the same as day 1 of ixazomib.

Drug: Dexamethasone

carfilzomib + dexamethasone

EXPERIMENTAL

Ixazomib will be administered PO at 4 mg on Days 1, 8 and 15 of a 28-day cycle. All other agents will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed. Patients that were on a 21-day cycle schedule will follow a 28-day cycle schedule and receive ixazomib on days 1, 8 and 15. Other drugs will be administered on the same days as they were given on their prior 21-day cycle schedule, except that, in the new 28-day schedule, day 1 of other drugs will be the same as day 1 of ixazomib.

Drug: Dexamethasone

bortezomib + lenalidomide + dexamethasone

EXPERIMENTAL

Ixazomib will be administered PO at 4 mg on Days 1, 8 and 15 of a 28-day cycle. All other agents will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed. Patients that were on a 21-day cycle schedule will follow a 28-day cycle schedule and receive ixazomib on days 1, 8 and 15. Other drugs will be administered on the same days as they were given on their prior 21-day cycle schedule, except that, in the new 28-day schedule, day 1 of other drugs will be the same as day 1 of ixazomib.

Drug: Dexamethasone; Drug: Lenalidomide

carfilzomib + lenalidomide + dexamethasone

EXPERIMENTAL

Ixazomib will be administered PO at 4 mg on Days 1, 8 and 15 of a 28-day cycle. All other agents will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed. Patients that were on a 21-day cycle schedule will follow a 28-day cycle schedule and receive ixazomib on days 1, 8 and 15. Other drugs will be administered on the same days as they were given on their prior 21-day cycle schedule, except that, in the new 28-day schedule, day 1 of other drugs will be the same as day 1 of ixazomib.

Drug: Dexamethasone; Drug: Lenalidomide

bortezomib + cyclophosphamide + dexamethasone

EXPERIMENTAL

MTD determination. Ixazomib will be administered on Days 1, 8 and 15 of a 28-day cycle at a starting dose of 3 mg in Cycle 1, and then intra-patient dose-escalation will proceed to 4 mg in Cycle 2. All other agents will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed. Patients that were on a 21-day cycle schedule will follow a 28-day cycle schedule and receive ixazomib on days 1, 8 and 15. Other drugs will be administered on the same days as they were given on their prior 21-day cycle schedule, except that, in the new 28-day schedule, day 1 of other drugs will be the same as day 1 of ixazomib.

Drug: Cyclophosphamide; Drug: Dexamethasone

bortezomib + cyclophosphamide + ascorbic acid

EXPERIMENTAL

MTD determination. Ixazomib will be administered on Days 1, 8 and 15 of a 28-day cycle at a starting dose of 3 mg in Cycle 1, and then intra-patient dose-escalation will proceed to 4 mg in Cycle 2. All other agents will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed. Patients that were on a 21-day cycle schedule will follow a 28-day cycle schedule and receive ixazomib on days 1, 8 and 15. Other drugs will be administered on the same days as they were given on their prior 21-day cycle schedule, except that, in the new 28-day schedule, day 1 of other drugs will be the same as day 1 of ixazomib. Due to a potential drug-drug interaction between ixazomib and ascorbic acid, patients will receive ixazomib in the clinic in the morning and will be instructed to take ascorbic acid in the evening, followed by cyclophosphamide.

Drug: Cyclophosphamide; Dietary Supplement: Ascorbic acid

bortezomib + PLD + dexamethasone

EXPERIMENTAL

MTD determination. Ixazomib will be administered on Days 1, 8 and 15 of a 28-day cycle at a starting dose of 3 mg in Cycle 1, and then intra-patient dose-escalation will proceed to 4 mg in Cycle 2. All other agents will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed. Patients that were on a 21-day cycle schedule will follow a 28-day cycle schedule and receive ixazomib on days 1, 8 and 15. Other drugs will be administered on the same days as they were given on their prior 21-day cycle schedule, except that, in the new 28-day schedule, day 1 of other drugs will be the same as day 1 of ixazomib.

Drug: Dexamethasone; Drug: PLD

bortezomib + pomalidomide + dexamethasone

EXPERIMENTAL

Ixazomib will be administered PO at 4 mg on Days 1, 8 and 15 of a 28-day cycle. All other agents will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed. Patients that were on a 21-day cycle schedule will follow a 28-day cycle schedule and receive ixazomib on days 1, 8 and 15. Other drugs will be administered on the same days as they were given on their prior 21-day cycle schedule, except that, in the new 28-day schedule, day 1 of other drugs will be the same as day 1 of ixazomib.

Drug: Dexamethasone; Drug: Pomalidomide

carfilzomib + pomalidomide + dexamethasone

EXPERIMENTAL

Ixazomib will be administered PO at 4 mg on Days 1, 8 and 15 of a 28-day cycle. All other agents will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed. Patients that were on a 21-day cycle schedule will follow a 28-day cycle schedule and receive ixazomib on days 1, 8 and 15. Other drugs will be administered on the same days as they were given on their prior 21-day cycle schedule, except that, in the new 28-day schedule, day 1 of other drugs will be the same as day 1 of ixazomib.

Drug: Dexamethasone; Drug: Pomalidomide

Interventions

Melphalan DRUG

Melphalan will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed (it varies with each patient).

Also known as: Phenylalanine mustard, Alkeran

bortezomib + melphalan + prednisone

Prednisone DRUG

Prednisone will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed (it varies with each patient).

Also known as: Cortan, Deltasone, Orasone, Prednisone Intensol, Sterapred, Sterapred DS

bortezomib + melphalan + prednisone

Cyclophosphamide DRUG

Cyclophosphamide will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed (it varies with each patient).

Also known as: Cytoxan, CPM, CTX, CYT

bortezomib + cyclophosphamide + ascorbic acid; bortezomib + cyclophosphamide + dexamethasone

Dexamethasone DRUG

Dexamethasone will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed (it varies with each patient).

Also known as: Decadron, Dexamethasone Intensol, Dexpak Taperpak

bortezomib + PLD + dexamethasone; bortezomib + cyclophosphamide + dexamethasone; bortezomib + dexamethasone; bortezomib + lenalidomide + dexamethasone; bortezomib + pomalidomide + dexamethasone; carfilzomib + dexamethasone; carfilzomib + lenalidomide + dexamethasone; carfilzomib + pomalidomide + dexamethasone

Ascorbic acid DIETARY_SUPPLEMENT

Vitamin C will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed (it varies with each patient).

Also known as: Vitamin C

bortezomib + cyclophosphamide + ascorbic acid

PLD DRUG

Pegylated liposomal doxorubicin will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed (it varies with each patient).

Also known as: ATI-0918, doxorubicin hydrochloride liposome, doxorubicin hydrochloride liposome injection, liposomal adriamycin, liposomal doxorubicin, liposomal doxorubicin hydrochloride, liposome-encapsulated doxorubicin, pegylated doxorubicin HCl liposome, Pegylated Liposomal Doxorubicin, S-Liposomal Doxorubicin, Stealth Liposomal Doxorubicin, DOXIL, Dox-SL, Evacet, LipoDox

bortezomib + PLD + dexamethasone

Lenalidomide DRUG

Lenalidomide will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed (it varies with each patient).

Also known as: Revlimid

bortezomib + lenalidomide + dexamethasone; carfilzomib + lenalidomide + dexamethasone

Pomalidomide DRUG

Pomalidomide will be administered at the same schedule and dose intensity as those of the last PI-containing treatment the patient failed (it varies with each patient).

Also known as: Pomalyst

bortezomib + pomalidomide + dexamethasone; carfilzomib + pomalidomide + dexamethasone

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
• Patients must have a diagnosis of MM, based on standard criteria as follows:
• Major criteria:
• plasmacytomas on tissue biopsy
• bone marrow plasmacytosis (greater than 30% plasma cells)
• monoclonal immunoglobulin spike on serum electrophoresis IgG greater than 3.5 g/dL or IgA greater than 2.0 g/dL; kappa or lambda light chain excretion greater than 1 g/day on 24 hour urine protein electrophoresis
• Minor criteria:
• bone marrow plasmacytosis (10% to 30% plasma cells)
• monoclonal immunoglobulin present but of lesser magnitude than given under major criteria
• lytic bone lesions
• normal IgM less than 50 mg/dL, IgA less than 100 mg/dL, or IgG less than 600 mg/dL
• Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:
• any 2 of the major criteria
• major criterion 1 plus minor criterion 2, 3, or 4
• major criterion 3 plus minor criterion 1 or 3

You may not qualify if:

• Patient has been diagnosed with:
• Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M protein) and skin changes (POEMS) syndrome.3
• Primary amyloidosis
• Plasma cell leukemia
• Severe hypercalcemia, i.e., serum calcium = 12 mg/dL (3.0 mmol/L) corrected for albumin
• Diagnosed or treated for another malignancy within 3 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanomatous skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• Impaired cardiac function or clinically significant cardiac diseases, including myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) Class II or greater heart failure, uncontrolled angina, clinically significant pericardial disease, severe uncontrolled ventricular arrhythmias, echocardiogram or multigated acquisition scan (MUGA) evidence of left ventricular ejection fraction (LVEF) below institutional normal within 28 days prior to enrollment, electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant
• Patient has peripheral neuropathy grade 3 or higher or Grade 2 with pain on clinical examination during the screening period
• Patient has received the following prior therapy:
• Chemotherapy within 21 days of enrollment (6 weeks for nitrosoureas)
• Corticosteroids (\>10 mg/day prednisone or equivalent) within 21 days of enrollment
• Immunotherapy or antibody therapy as well as thalidomide, pomalidomide, lenalidomide, arsenic trioxide, carfilzomib, or bortezomib within 21 days before enrollment
• 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

Sponsors & Collaborators

• Oncotherapeutics: lead
• Takeda: collaborator

Study Sites (12)

Comprehensive Blood and Cancer Center

Bakersfield, California, 93309, United States

Location

John Muir Health Clinical Research Center

Concord, California, 94520, United States

Location

California Cancer Associates for Research & Excellence (cCARE)

Encinitas, California, 92024, United States

Location

Robert A. Moss, MD, FACP, Inc

Fountain Valley, California, 92708, United States

Location

cCARE Fresno

Fresno, California, 93720, United States

Location

Comprehensive Cancer Center at Desert Regional Medical Center

Palm Springs, California, 92262, United States

Location

James Berenson, MD, Inc

West Hollywood, California, 90069, United States

Location

Cancer Specialists of North Florida

Fleming Island, Florida, 32003, United States

Location

Lewis Hall Singletary Oncology Center

Thomasville, Georgia, 31792, United States

Location

Oncology Specialists, SC

Niles, Illinois, 60714, United States

Location

Hattiesburg Clinic Hematology/Oncology

Hattiesburg, Mississippi, 39401, United States

Location

Vista Oncology

Olympia, Washington, 98502, United States

Location

MeSH Terms

Conditions

Multiple Myeloma; Recurrence

Interventions

Melphalan; Prednisone; Cyclophosphamide; Dexamethasone; Calcium Dobesilate; Ascorbic Acid; 1-dodecylpyridoxal; liposomal doxorubicin; Doxorubicin; Lenalidomide; pomalidomide

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; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Phosphoramide Mustards; Phosphoramides; Organophosphorus Compounds; Pregnadienetriols; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Hydroxy Acids; Carbohydrates; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Aminoglycosides; Glycosides; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• James R Berenson, MD

  James R. Berenson MD, Inc.

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 30, 2014
• First Posted: August 1, 2014
• Study Start: September 1, 2014
• Primary Completion: January 19, 2018
• Study Completion: March 6, 2018
• Last Updated: October 31, 2023

Record last verified: 2023-10

Locations

US (12)