Study of Oral MLN9708 in Combination With Melphalan and Prednisone in Patients With Newly Diagnosed Multiple Myeloma - Full Text View

Purpose

This will be a phase 1/2, multicenter, 2-arm, open-label study using the oral formulation of MLN9708 when added to standard melphalan and prednisone (MP) treatment. Both phases of the study will include patients who have newly diagnosed multiple myeloma and are ineligible for high-dose therapy plus stem cell transplantation because of age (≥65 years of age) or coexisting conditions and for whom standard MP treatment is indicated.

Note: Phase 2 of the trial will be randomized.

Condition	Intervention	Phase
Multiple Myeloma	Drug: MLN9708 plus Melphalan and Prednisone	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	An Open-Label, Dose-Escalation, Phase 1/2 Study of the Oral Form of MLN9708, a Next-Generation Proteasome Inhibitor, Administered in Combination With a Standard Care Regimen of Melphalan and Prednisone in Patients With Newly Diagnosed Multiple Myeloma Requiring Systemic Treatment

Resource links provided by NLM:

MedlinePlus related topics: Cancer Multiple Myeloma Steroids

Drug Information available for: Prednisone Melphalan Melphalan hydrochloride

U.S. FDA Resources

Further study details as provided by Millennium Pharmaceuticals, Inc.:

Primary Outcome Measures:

Maximum Tolerated Dose and Recommended phase 2 dose of MLN9708 (phase 1) [ Time Frame: Dose Limiting Toxicities determined in Cycle 1 and adverse events monitored throughout the study will inform the recommended phase 2 dose, approximately 2 years ] [ Designated as safety issue: Yes ]
Based on toxicity and efficacy outcomes
Number of patients with a complete response and very good partial response (phase 2) [ Time Frame: During the induction period, approximately 1 year ] [ Designated as safety issue: No ]
Combined response rate

Secondary Outcome Measures:

Maximum inhibition (Emax) and time of occurrence of Emax (TEmax) (phase 1) [ Time Frame: At multiple time points during cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study ] [ Designated as safety issue: No ]
Whole blood 20S proteasome inhibition parameters
Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and area under the plasma concentration-time curve (AUC) (phase 1) [ Time Frame: At multiple time points during cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study ] [ Designated as safety issue: No ]
Single and multiple dose plasma pharmacokinetics
Number of patients with response, including Complete Response, Very Good Partial Response and Partial Response (phase 1 and 2) [ Time Frame: Duration of treatment and then every 12 weeks thereafter until disease progression or initiation of subsequent antineoplastic therapy, expected duration approximately 4 years ] [ Designated as safety issue: No ]
Overall reponse rate
Time to response (phase 2) [ Time Frame: From the date of enrollment to the date of the first documented response during the induction period, expected average of up to 1 year ] [ Designated as safety issue: No ]
Duration of response (phase 2) [ Time Frame: From the date of first response to the date of disease progression, approximately 4 years ] [ Designated as safety issue: No ]
Time to progression (phase 2) [ Time Frame: From date of enrollment to the date of first documented disease progression, approximately 4 years ] [ Designated as safety issue: No ]
Time to next therapy (phase 2) [ Time Frame: From the date of enrollment to the date of subsequent antineoplastic therapy, approximately 4 years ] [ Designated as safety issue: No ]
Number of patients with progression free survival (phase 2) [ Time Frame: From the date of enrollment to the date of first documented disease progression or death, approximately 4 years ] [ Designated as safety issue: No ]
Number of patients with overall survival (phase 2) [ Time Frame: From date of enrollment to date of death, approximately 4 years ] [ Designated as safety issue: No ]
Number of all adverse events (phase 2) [ Time Frame: From first dose of study drug through 30 days after last dose of study drug or until the start of subsequent antineoplastic therapy, approximately 2 years and 30 days ] [ Designated as safety issue: Yes ]
Assessments of Quality of Life (phase 2) [ Time Frame: At screening, Day 1 of each treatment cycle, and Days 1 and 15 of each maintenance cycle, approximately 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment:	164
Study Start Date:	June 2011
Estimated Study Completion Date:	January 2015
Estimated Primary Completion Date:	October 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Arm A MLN9708 Twice Weekly plus Melphalan and Prednisone every 42 days for up to 9 cycles followed by maintenance therapy with MLN9708 once weekly	Drug: MLN9708 plus Melphalan and Prednisone Ph 1: Patients will receive escalating doses of MLN9708 on Days 1,4,8,11,22,25,29,&32 of a 42-day cycle & fixed doses of melphalan (9mg/m2) & prednisone (60mg/m2) on Days 1-4 of every cycle. Treatment repeats every 42 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or disease responding to treatment with an acceptable toxicity profile will continue treatment in the maintenance therapy portion of the study. Ph 2: Patients will receive MLN9708 at the maximum tolerated dose or recommended phase 2 dose on Days 1,4,8,11,22,25,29,&32 of a 42-day cycle & melphalan (9mg/m2) & prednisone (60mg/m2) on Days 1-4 of every cycle. Treatment repeats every 42 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or disease responding to treatment with an acceptable toxicity profile will continue treatment in the maintenance therapy portion of the study.
Experimental: Arm B MLN9708 Once Weekly plus Melphalan and Prednisone every 28 days for up to 12 cycles followed by maintenance therapy with MLN9708 once weekly	Drug: MLN9708 plus Melphalan and Prednisone Ph 1: Patients will receive escalating doses of MLN9708 on Days 1, 8, and 15 and fixed doses of melphalan (6mg/m2) and prednisone (60mg/m2) on Days 1-4 of a 28-day cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or disease responding to treatment with an acceptable toxicity profile will continue treatment in the maintenance therapy portion of the study. Ph 2: Patients will receive MLN9708 at the maximum tolerated dose or recommended phase 2 dose on Days 1, 8, and 15 and melphalan (6mg/m2) and prednisone (60mg/m2) on Days 1 through 4 of a 28-day cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or disease responding to treatment with an acceptable toxicity profile will continue treatment in the maintenance therapy portion of the study.

Arms

Assigned Interventions

Experimental: Arm A

MLN9708 Twice Weekly plus Melphalan and Prednisone every 42 days for up to 9 cycles followed by maintenance therapy with MLN9708 once weekly

Drug: MLN9708 plus Melphalan and Prednisone

Ph 1: Patients will receive escalating doses of MLN9708 on Days 1,4,8,11,22,25,29,&32 of a 42-day cycle & fixed doses of melphalan (9mg/m2) & prednisone (60mg/m2) on Days 1-4 of every cycle. Treatment repeats every 42 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or disease responding to treatment with an acceptable toxicity profile will continue treatment in the maintenance therapy portion of the study.

Ph 2: Patients will receive MLN9708 at the maximum tolerated dose or recommended phase 2 dose on Days 1,4,8,11,22,25,29,&32 of a 42-day cycle & melphalan (9mg/m2) & prednisone (60mg/m2) on Days 1-4 of every cycle. Treatment repeats every 42 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or disease responding to treatment with an acceptable toxicity profile will continue treatment in the maintenance therapy portion of the study.

Experimental: Arm B

MLN9708 Once Weekly plus Melphalan and Prednisone every 28 days for up to 12 cycles followed by maintenance therapy with MLN9708 once weekly

Drug: MLN9708 plus Melphalan and Prednisone

Ph 1: Patients will receive escalating doses of MLN9708 on Days 1, 8, and 15 and fixed doses of melphalan (6mg/m2) and prednisone (60mg/m2) on Days 1-4 of a 28-day cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or disease responding to treatment with an acceptable toxicity profile will continue treatment in the maintenance therapy portion of the study.

Ph 2: Patients will receive MLN9708 at the maximum tolerated dose or recommended phase 2 dose on Days 1, 8, and 15 and melphalan (6mg/m2) and prednisone (60mg/m2) on Days 1 through 4 of a 28-day cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or disease responding to treatment with an acceptable toxicity profile will continue treatment in the maintenance therapy portion of the study.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Male or female patient for whom standard melphalan prednisone (MP) treatment is indicated and who is not a candidate for high-dose therapy plus stem cell transplantation (HDT-SCT) for 1 of the following reasons: the patient is 65 years of age or older OR the patient is less than 65 years of age but has significant comorbid condition(s) that are likely to have a negative impact on tolerability of HDT-SCT
Symptomatic multiple myeloma or asymptomatic myeloma with myeloma-related organ damage diagnosed according to standard criteria
Measurable disease as specified in study protocol
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
Must have adequate hematologic, liver, and renal function
Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse
Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse
Voluntary written consent

Exclusion Criteria

Peripheral neuropathy that is greater or equal to Grade 2
Female patients who are lactating or pregnant
Major surgery or radiotherapy within 14 days before the first dose of study drug
Uncontrolled infection requiring systematic antibiotics
Diarrhea (> Grade 1)
Prior systemic therapy for multiple myeloma, including investigational drugs (prior treatment with corticosteroids or localized radiation therapy dose not disqualify the patient)
Central nervous system involvement
Cardiac status as described in protocol
Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of MLN9708
Diagnosis of smoldering multiple myeloma, Waldenstrom's macroglobulinemia, POEMS syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome
Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease with the exception of nonmelanoma skin cancer or any completely resected carcinoma in situ
Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01335685

Contacts

Contact: For an updated listing of recruitment sites contact: Millennium Medical and Drug Information Center

1-877-674-3784

medical@mlnm.com

Locations

United States, Georgia
Emory University	Recruiting
Atlanta, Georgia, United States, 30322
United States, New Hampshire
Dartmouth Hitchcock Medical Center	Recruiting
Lebanon, New Hampshire, United States, 03756
United States, West Virginia
Mary Babb Randolph Cancer Center/WVU	Recruiting
Morgantown, West Virginia, United States, 26506
Canada, British Columbia
Vancouver General Hospital	Recruiting
Vancouver, British Columbia, Canada, V5Z4E6
Canada, Ontario
University Health Network, Princess Margaret Hospital	Recruiting
Toronto, Ontario, Canada, M5G 2M9
Canada
CHA/Québec-Hôpital Enfant-Jésus	Recruiting
Quebec, Canada, G1J 1Z4
Czech Republic
Fakultni nemocnice Brno	Recruiting
Brno, Czech Republic, 625 00
Všeobecná fakultní nemocnice v Praze	Recruiting
Prague, Czech Republic, 128 08
Italy
Azienda Ospedaliera di Rilievo Nazionale A. Cardarelli	Recruiting
Napoli, Italy, 80131
Russian Federation
State Healthcare Institution "Republican Hospital named after V.A. Baranov"	Recruiting
Petrozavodsk, Russian Federation, 185019
Federal State Institution "Russian Scientific and Research Institute of Hematology and Transfusiology" of Federal Medical Biological Agency	Recruiting
St. Petersburg, Russian Federation, 191024
Spain
Hospital Universitari Germans I Pujol	Recruiting
Barcelona, Spain, 08916
Hospital Clínic i Provincial de Barcelona	Recruiting
Barcelona, Spain, 20014
Hospital Universitario de La Princesa	Recruiting
Madrid, Spain, 28006
Hospital Universitario de Salamanca	Recruiting
Salamanca, Spain, 37007
Hospital Donosti	Recruiting
San Sebastian, Spain, 20014
Hospital Universitario Virgen del Rocio	Recruiting
Sevilla, Spain, 41013
United Kingdom
Centre for Experimental Cancer Medicine/Bart's Cancer Institute	Recruiting
London, UK, United Kingdom, EC1M6BQ
University College London	Recruiting
London, UK, United Kingdom, WC1E 6DB
Royal Bournemouth General Hospital	Recruiting
Bournemouth, United Kingdom, BH7 7DW
Addenbrooke's Hospital	Recruiting
Cambridge, United Kingdom, BH7 7DW

Sponsors and Collaborators

Millennium Pharmaceuticals, Inc.

Investigators

Study Director:

Medical Monitor

Millennium Pharmaceuticals, Inc.

More Information

No publications provided

Responsible Party:	Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT01335685 History of Changes
Other Study ID Numbers:	C16006, 2010-023772-71
Study First Received:	April 8, 2011
Last Updated:	December 13, 2012
Health Authority:	United States: Food and Drug Administration European Union: European Medicines Agency

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
Melphalan

Prednisone
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal

ClinicalTrials.gov processed this record on June 17, 2013