Alisertib (MLN8237) in Participants With Ovarian, Fallopian Tube or Peritoneal Cancer Preceded by Phase 1 Study of MLN8237 Plus Paclitaxel Treatment of Ovary or Breast Cancer

NCT ID: NCT01091428

Last Updated: 2018-06-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 191 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-04-16
• Study Completion Date: 2017-07-19

Brief Summary

This is an open-label, multicenter study with a nonrandomized Phase 1 portion and an open-label, randomized, Phase 2 portion evaluating MLN8237 in combination with weekly paclitaxel in adult female participants with advanced breast cancer (Phase 1 portion only) and recurrent ovarian cancer (both Phase 1 and Phase 2 portions).

Detailed Description

The drug tested in this study was called alisertib. Alisertib was tested to treat people who have ovarian and breast cancer. This study looked at safety, any anti-tumor effect, and it also determined a recommended dose of alisertib plus paclitaxel to take into further studies. Pharmacokinetic blood samples were studied to characterize any effects on the concentration of each of the drugs when administered together.

The study enrolled 191 patients. Participants with Breast Cancer and Ovarian Cancer received one of the following escalating doses of alisertib in combination with paclitaxel in the Phase 1 lead-in portion of the study:

• Alisertib 10 mg BID + Paclitaxel 80 mg/m^2
• Alisertib 20 mg BID + Paclitaxel 80 mg/m^2
• Alisertib 20 mg BID + Paclitaxel 60 mg/m^2
• Alisertib 30 mg BID + Paclitaxel 60 mg/m^2
• Alisertib 40 mg BID + Paclitaxel 60 mg/m^2
• Alisertib 50 mg BID + Paclitaxel 60 mg/m^2

Once the maximum tolerated dose (MTD)/ recommended phase 2 dose (RP2D) was determined, participants were randomized to receive the following treatments in the Phase 2 portion of the study:

• Alisertib 40 mg BID + Paclitaxel 60 mg/m^2
• Paclitaxel 80 mg/m^2

This multi-center trial was conducted in the United States, Poland and France. The overall time to participate in this study was approximately 5 years. Participants made multiple visits to the clinic, and who did not experience disease progression (PD) were followed off-treatment once every 8 weeks until the occurrence of 110 progression-free survival (PFS) events.

Conditions

Ovarian Carcinoma; Fallopian Tube Cancer; Peritoneal Cancer; Breast Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Alisertib (Phase 1 - Ovarian cancer)

Participants with ovarian cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m\^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).

Group Type: EXPERIMENTAL

Alisertib

Intervention Type: DRUG

Alisertib tablets

Paclitaxel

Intervention Type: DRUG

Paclitaxel intravenous infusion

Alisertib (Phase 1 - Breast cancer)

Participants with breast cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m\^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).

Group Type: EXPERIMENTAL

Alisertib

Intervention Type: DRUG

Alisertib tablets

Paclitaxel

Intervention Type: DRUG

Paclitaxel intravenous infusion

Alisertib 40 mg BID+Paclitaxel 60 mg/m^2 (Phase 2)

Alisertib 40 mg, orally, BID on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m\^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

Group Type: EXPERIMENTAL

Alisertib

Intervention Type: DRUG

Alisertib tablets

Paclitaxel

Intervention Type: DRUG

Paclitaxel intravenous infusion

Paclitaxel 80 mg/m^2 (Phase 2)

Paclitaxel 80 mg/m\^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

Group Type: EXPERIMENTAL

Paclitaxel

Intervention Type: DRUG

Paclitaxel intravenous infusion

Interventions

Alisertib

Alisertib tablets

Intervention Type: DRUG

Paclitaxel

Paclitaxel intravenous infusion

Intervention Type: DRUG

Other Intervention Names

MLN8237

Eligibility Criteria

Inclusion Criteria

• Female participants 18 years or older
• Previously treated, metastatic or locally recurrent malignancy with 1 of the following diagnoses, which has been confirmed histologically or cytologically: adenocarcinoma of the breast (Phase 1 only), recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma (Phase 1 and 2)
• In the Phase 1 portion of the study, participants with breast cancer must have received treatment with at least 1 but no more than 4 prior chemotherapy regimens not including regimens received in the neoadjuvant and/or adjuvant setting
• Participants with breast cancer must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• No antineoplastic therapy or radiotherapy within 3 weeks before enrollment (2 weeks for regimens with recovery expected within 7 to 14 days) and recovered from toxicities of prior therapy (except alopecia); the participant must have recovered from all treatment-related toxicities and must have evidence of progressive disease (PD) or persistent disease
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Adequate bone marrow, liver and renal function
• Postmenopausal at least 1 year, OR Surgically sterile, OR If childbearing potential, agree to 2 effective methods of nonhormonal contraception, or agree to completely abstain from heterosexual intercourse
• Able to provide written informed consent
• Willing to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures
• Suitable venous access

• Prior treatments must have included a platinum and a taxane; the most recent treatment need not be a platinum-containing or taxane-containing regimen
• Disease must have recurred ≤ 12 months after discontinuation of platinum therapy
• Participants who previously received weekly taxane are potentially eligible, provided that they did not progress during therapy or within 3 months of completing therapy
• Participants with platinum-refractory disease, as defined by progression during primary or subsequent platinum-based therapy or persistent radiographic disease after primary or subsequent platinum-based therapy, will be included
• Participants must have measurable disease in target lesions or assessable disease (defined by cancer antigen-125 - CA-125 per protocol), and disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or modified Gynecologic Cancer Intergroup (GCIG) CA-125 criteria

Exclusion Criteria

• Prior treatment with an Aurora A-targeted agent (including MLN8237)
• Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of MLN8237 and during the study
• Treatment with more than 4 cytotoxic chemotherapy regimens in the metastatic setting; prior therapy cannot include more than 2 prior taxane-containing regimen. Current use of tamoxifen, thalidomide, or any agent used as maintenance or consolidation therapy for OC.
• Known hypersensitivity to Cremophor® EL, paclitaxel or its components
• Prior history of ≥ Grade 2 neurotoxicity or any toxicity requiring discontinuation from taxane chemotherapy that is not resolved to ≤ Grade 1
• Comorbid or unresolved toxicity that would preclude administration of weekly paclitaxel
• Primary central nervous system malignancy or carcinomatous meningitis
• Symptomatic brain metastasis
• Inability to swallow oral medications or maintain a fast
• History of hemorrhagic or thrombotic cerebrovascular event in past 12 months
• Surgery within 3 weeks before study enrollment and not fully recovered
• Diagnosis or treatment of another malignancy within 2 years preceding first dose of MLN8237 and have any evidence of residual disease except nonmelanoma skin cancer or in situ malignancy completely resected
• Pregnant or lactating
• Serious illness that could interfere with protocol completion
• Investigational treatment 21 days prior to first dose of MLN8237
• Prior allogeneic bone marrow or organ transplantation
• Infection requiring systemic antibiotic therapy within 14 days prior to first dose of MLN8237
• Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C
• Radiotherapy to > 25% bone marrow or whole pelvic radiotherapy
• Requirement for constant administration of proton pump inhibitor, H2 antagonist, or pancreatic enzymes. Intermittent uses of antacids of H2 antagonists are allowed

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Millennium Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Monitor

Role: STUDY_DIRECTOR

Millennium Pharmaceuticals, Inc.

Locations

The Bronx, New York, United States

Philadelphia, Pennsylvania, United States

Houston, Texas, United States

Seattle, Washington, United States

Countries

United States

References

Falchook G, Coleman RL, Roszak A, Behbakht K, Matulonis U, Ray-Coquard I, Sawrycki P, Duska LR, Tew W, Ghamande S, Lesoin A, Schwartz PE, Buscema J, Fabbro M, Lortholary A, Goff B, Kurzrock R, Martin LP, Gray HJ, Fu S, Sheldon-Waniga E, Lin HM, Venkatakrishnan K, Zhou X, Leonard EJ, Schilder RJ. Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial. JAMA Oncol. 2019 Jan 1;5(1):e183773. doi: 10.1001/jamaoncol.2018.3773. Epub 2019 Jan 10.

Reference Type: DERIVED

PMID: 30347019 (View on PubMed)

Other Identifiers

2009-011428-79

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1191-6584

Identifier Type: REGISTRY

Identifier Source: secondary_id

C14008

Identifier Type: -

Identifier Source: org_study_id