Phase 1 Pharmacokinetics Study of Oral MLN9708 in Patients With Advanced Nonhematologic Malignancies or Lymphoma - Full Text View

Purpose

This is an open-label, multicenter, sequential, 4-arm, phase 1 study of oral MLN9708 designed to assess drug-drug interaction with ketoconazole (Arm 1), the relative bioavailability of 2 capsule formulations of MLN9708 (Arm 2), food effect (Arm 3), and drug-drug interaction with rifampin (Arm 4) in patients with advanced nonhematologic malignancies or lymphoma.

Condition	Intervention	Phase
Nonhematologic Malignancies Lymphoma	Drug: MLN9708 Capsule B formulation Drug: MLN9708 Capsule A formulation Drug: ketoconazole Drug: rifampin	Phase 1

Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Crossover Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase 1 Study of Oral MLN9708 to Assess Drug-Drug Interaction With Ketoconazole, Relative Bioavailability, Food Effect, Drug-Drug Interaction With Rifampin, and Safety and Tolerability in Patients With Advanced Nonhematologic Malignancies or Lymphoma

Resource links provided by NLM:

MedlinePlus related topics: Cancer Drug Reactions Lymphoma

Drug Information available for: Rifampin Ketoconazole

U.S. FDA Resources

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

Primary Outcome Measures:

Arm 1: Ratio of geometric mean Cmax and AUC0-tlast of MLN9708 administered as Capsule B formulation with ketoconazole versus when administered as a single agent and 90% confidence intervals (CI) [ Time Frame: Cycle 1: Days 1-28 ] [ Designated as safety issue: No ]
Arm 1: Effect of ketoconazole on the single-dose pharmacokinetics of MLN9708 administered as Capsule B formulation
Arm 2: Ratio of geometric mean Cmax and AUC0-tlast of Capsule B formulation versus Capsule A formulation and 90% CI [ Time Frame: Cycle 1: Days 1-28 ] [ Designated as safety issue: No ]
Arm 2: Relative bioavailability of a Capsule B formulation of MLN9708 in reference to Capsule A formulation
Arm 3: Capsule B formulation ratio of geometric mean Cmax and AUC0-tlast of MLN9708 administered as Capsule B formulation with food versus without food and 90% CI [ Time Frame: Cycle 1: Days 1-28 ] [ Designated as safety issue: No ]
Arm 3: Effect of food on the single-dose pharmacokinetics of MLN9708 administered as Capsule B formulation
Arm 4: Ratio of geometric mean Cmax and AUC0-tlast of MLN9708 administered as Capsule B with rifampin versus when administered as a single agent and 90% confidence intervals (CI) [ Time Frame: Cycle 1: Days 1-28 ] [ Designated as safety issue: No ]
Arm 4: To characterize the effect of rifampin on the single-dose pharmacokinetics of MLN9708 administered as Capsule B formulation

Secondary Outcome Measures:

Adverse events, serious adverse events, assessments of clinical laboratory values, and vital sign measurements [ Time Frame: From the time informed consent is signed through 30 days after the last dose of study drug, approximately 13 months ] [ Designated as safety issue: Yes ]
Safety and tolerability of MLN9708
Measures of disease response according to standard criteria [ Time Frame: Q2 cycles for first 4 cycles, then Q3 cycles, approximately 13 months ] [ Designated as safety issue: No ]

Estimated Enrollment:	90
Study Start Date:	November 2011
Estimated Study Completion Date:	December 2013
Estimated Primary Completion Date:	October 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Arm 1 (ketoconazole drug-drug interaction study) Patients receive a single 2.5-mg oral dose of MLN9708 Capsule B formulation on Day 1 and Day 15 during Cycle 1. Patients receive concomitant oral ketoconazole, a strong CYP3A inhibitor, at a dose of 400-mg once daily on Days 12 through 25 during Cycle 1.	Drug: MLN9708 Capsule B formulation Applicable to all Arms: After completion of Cycle 1, patients receive a 4.0- mg dose of MLN9708 Capsule B formulation on Days 1, 8, and 15 of a 28-day schedule; however, starting with Cycle 4 and beyond patients will have the option of escalating to the 5.3-mg dose at the discretion of the investigator and the Millennium clinician. The maximum duration of treatment is 12 months after completion of Cycle 1 (13 months in total) unless it is determined that a patient would derive benefit from continued therapy beyond 12 cycles. Drug: ketoconazole
Experimental: Arm 2 (relative bioavailability study) Patients receive a single oral dose of MLN9708 Capsule A or Capsule B formulation on Day 1, followed by a single dose of 4.0-mg of the alternate formulation (Capsule B formulation or A) on Day 15 of a 28-days pharmacokinetic cycle.	Drug: MLN9708 Capsule B formulation Applicable to all Arms: After completion of Cycle 1, patients receive a 4.0- mg dose of MLN9708 Capsule B formulation on Days 1, 8, and 15 of a 28-day schedule; however, starting with Cycle 4 and beyond patients will have the option of escalating to the 5.3-mg dose at the discretion of the investigator and the Millennium clinician. The maximum duration of treatment is 12 months after completion of Cycle 1 (13 months in total) unless it is determined that a patient would derive benefit from continued therapy beyond 12 cycles. Drug: MLN9708 Capsule A formulation
Experimental: Arm 3 (food effect study) Patients receive a single 4.0-mg oral dose of MLN9708 as Capsule B formulation with or without a standard high-fat breakfast on Day (D) 1 of Cycle (C) 1, followed by administration under the alternate food intake condition on D 15 of C 1. Fasted treatment: D 1 or 15 dose administered with ~ 8-oz of water following an overnight fast, including no medications, of ~10 hrs. Fed treatment: following an overnight fast, including no medications, of ~10 hrs, patients start breakfast 30 min prior to the administration of the D 1 or 15 dose. MLN9708 is administered 30 min after the start of the meal with ~8-oz of water. In both treatments, no food is allowed for at least 4 hrs postdose of the D 1 or 15 dose. Water is allowed except for 1 hr before and after drug administration.	Drug: MLN9708 Capsule B formulation Applicable to all Arms: After completion of Cycle 1, patients receive a 4.0- mg dose of MLN9708 Capsule B formulation on Days 1, 8, and 15 of a 28-day schedule; however, starting with Cycle 4 and beyond patients will have the option of escalating to the 5.3-mg dose at the discretion of the investigator and the Millennium clinician. The maximum duration of treatment is 12 months after completion of Cycle 1 (13 months in total) unless it is determined that a patient would derive benefit from continued therapy beyond 12 cycles.
Experimental: Arm 4 (rifampin drug-drug interaction study) Patients receive a single 4.0-mg oral dose of MLN9708 Capsule B formulation on Day 1 and Day 15 during Cycle 1, the 28-day PK cycle. Patients receive concomitant oral rifampin, a strong CYP3A inducer, at a dose of 600 mg once daily on Days 8 through 21 during Cycle 1.	Drug: MLN9708 Capsule B formulation Applicable to all Arms: After completion of Cycle 1, patients receive a 4.0- mg dose of MLN9708 Capsule B formulation on Days 1, 8, and 15 of a 28-day schedule; however, starting with Cycle 4 and beyond patients will have the option of escalating to the 5.3-mg dose at the discretion of the investigator and the Millennium clinician. The maximum duration of treatment is 12 months after completion of Cycle 1 (13 months in total) unless it is determined that a patient would derive benefit from continued therapy beyond 12 cycles. Drug: rifampin

Eligibility

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

Criteria

Inclusion Criteria:

Male or female patients 18 years or older
Patients must have a diagnosis of histologically or cytologically confirmed metastatic and/or advanced solid tumor malignancy or lymphoma for which no effective standard treatment is available
Female patients who are postmenopausal at least 1 year, OR surgically sterile, OR if of childbearing potential, agree to practice 2 effective methods of contraception, at the same time from the time of signing the consent form through 90 days after the last dose of study drug, or agree to practice true abstinence
Male patients, even if surgically sterilized, 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
Voluntary written informed consent
Clinical laboratory values as specified in protocol
Suitable venous access
Recovered (ie, < Grade 1 toxicity or patient's baseline status) from the reversible effects of prior anticancer therapy

Exclusion Criteria:

Peripheral neuropathy > Grade 2 on clinical examination
Systemic treatment with strong inhibitors of CYP1A2, strong inhibitors of CYP3A, or strong CYP3A inducers or use of Ginkgo biloboa or St. John's wort within 14 days before the first dose of MLN9708
Patient has symptomatic brain metastasis. Patients with brain metastases must: have stable neurologic status following surgery or radiation for at least 2 weeks after completion of the definitive therapy; AND be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
Female patients who are pregnant or lactating
Serious illness that could interfere with protocol completion
Autologous stem cell transplant within 6 months before Day 1 of Cycle 1, or prior allogeneic stem cell transplant at any time
Prior treatment with rituximab or other unconjugated any antibody treatment within 42 days (21 days if there is clear evidence of progressive disease or immediate treatment is mandated)
Ongoing treatment with corticosteroids
Radiotherapy within 21 days before the first dose of study drug
Major surgery within 14 days before the first dose of study drug
Infection requiring systemic antibiotic therapy or other serious infection within 14 days prior to first dose of study drug
Life-threatening illness unrelated to cancer
Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive, or suspected hepatitis C infection
Diagnosis or treatment of another malignancy within 2 years preceding first dose, OR previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
Evidence of uncontrolled cardiovascular conditions
QTc > 500 milliseconds on a 12-lead electrocardiogram (ECG)
Known gastrointestinal disease or procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty swallowing capsules; diarrhea > Grade 1 despite supportive therapy
Patients with gastric achlorhydria
Patients who have used any nicotine containing products within 14 days before the first dose of study drug (Arm 1 and Arm 4 only)
Treatment with any investigational products or systemic antineoplastic therapies within 21 days before the first dose of MLN9708

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01454076

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, California
San Diego Pacific Oncology & Hematology Assoc Inc.	Recruiting
San Diego, California, United States, 92024
UCLA Hematology-Oncology Santa Monica	Recruiting
Santa Monica, California, United States, 90404
United States, Indiana
IUPUI	Recruiting
Indianapolis, Indiana, United States, 46202
United States, Texas
Mary Crowley Cancer Research Centers	Recruiting
Dallas, Texas, United States, 75201
United States, Utah
University of Utah	Recruiting
Salt Lake City, Utah, United States, 84112

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:	NCT01454076 History of Changes
Other Study ID Numbers:	C16009
Study First Received:	October 13, 2011
Last Updated:	February 5, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by Millennium Pharmaceuticals, Inc.:

Cmax: maximum plasma concentration
AUC0-tlast: time zero to the time of the last quantifiable concentration

Additional relevant MeSH terms:

Neoplasms
Lymphoma
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Ketoconazole
Rifampin
14-alpha Demethylase Inhibitors
Enzyme Inhibitors

Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Antibiotics, Antitubercular
Anti-Bacterial Agents
Antitubercular Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on June 18, 2013