Clinical trial NCT01091428: 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
Official title: Randomized Phase 2 Study of MLN8237, an Aurora A Kinase Inhibitor, Plus Weekly Paclitaxel or Weekly Paclitaxel Alone in Patients With Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer, Preceded by a Phase 1 Portion in Patients With Ovarian or Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ovarian Carcinoma
Fallopian Tube Cancer
Peritoneal Cancer
Breast Carcinoma
Keywords: RECIST: Response Evaluation Criteria in Solid Tumors
OC: Ovarian Cancer
GCIG: Gynecologic Cancer Intergroup
Breast carcinoma (Phase 1)
Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2010-03-24
Enrollment: 191
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

Each participant must meet all of the following inclusion criteria to be enrolled in the study:

* 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

Specific Inclusion Criteria for participants with Recurrent Ovarian, Fallopian Tube or Peritoneal Cancer:

* 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:

Participants meeting any of the following exclusion criteria are not to be enrolled in the study:

* 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

Primary outcomes:
measure: Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) for Alisertib in Combination With Paclitaxel
timeFrame: Cycle 1 (Up to 28 days)
measure: Phase 1: MTD and RP2D for Paclitaxel in Combination With Alisertib
timeFrame: Cycle 1 (Up to 28 days)
measure: Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: First dose to 30 days past last dose (Up to 36 Months)
measure: Phase 1: Number of Participants With Clinically Significant Laboratory Values
timeFrame: First dose to 30 days past last dose (Up to 36 Months)
measure: Phase 1: Number of Participants With Clinically Significant Vital Sign Findings
timeFrame: First dose to 30 days past last dose (Up to 36 Months)
measure: Phase 1: Number of Participants With Hypersensitivity and Neurotoxicity
timeFrame: Baseline up to Month 36
measure: Phase 2: Progression-Free Survival (PFS)
timeFrame: At the end of Cycle 2 and at the completion of every 2 cycles until PD was documented or up to data cut-off: 12 August 2014 (approximately 24 months)
Secondary outcomes:
measure: Phase 1: Combined Best Overall Response Rate (ORR) in Participants With Recurrent Ovarian Cancer or Breast Cancer
timeFrame: At the end of Cycle 2 and at the completion of every 2 cycles until PD was documented or up to data cut-off: 12 August 2014 (approximately 24 months)
measure: Cmax: Maximum Observed Concentration for Alisertib in Phase 1
timeFrame: Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
measure: Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1
timeFrame: Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
measure: AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1
timeFrame: Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
measure: AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1
timeFrame: Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
measure: Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1
timeFrame: Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
measure: AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1
timeFrame: Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
measure: AUC∞: Area Under the Concentration-Time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1
timeFrame: Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
measure: t½: Terminal Half-Life for Paclitaxel in Phase 1
timeFrame: Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
measure: CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1
timeFrame: Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
measure: Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1
timeFrame: Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
measure: Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1
timeFrame: Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
measure: Phase 2: Combined Best Overall Response Rate (ORR)
timeFrame: At the end of Cycle 2 and at the completion of every 2 cycles until PD was documented or up to data cut-off: 12 August 2014 (approximately 24 months)
measure: Phase 2: Duration of Response (DOR)
timeFrame: Up to data-cut off: 12 August 2014 (approximately 24 months)
measure: Phase 2: Time to Disease Progression (TTP)
timeFrame: Up to data-cut off: 12 August 2014 (approximately 24 months)
measure: Phase 2: Overall Survival (OS)
timeFrame: Up to data-cut off: 12 August 2014 (approximately 24 months)
measure: Phase 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: First dose to 30 days past last dose (Up to 27 Months)
measure: Phase 2: Number of Participants With Clinically Significant Laboratory Values
timeFrame: First dose to 30 days past last dose (Up to 27 Months)
measure: Phase 2: Number of Participants With Clinically Significant Vital Sign Findings
timeFrame: First dose to 30 days past last dose (Up to 27 Months)
Other outcomes:
measure: Banked Tumor Specimens for Candidate Markers of Response to Alisertib and Taxanes
timeFrame: Up to 24 Months
Locations:
city: Bronx
country: United States
state: New York
city: Philadelphia
country: United States
state: Pennsylvania
city: Houston
country: United States
state: Texas
city: Seattle
country: United States
state: Washington
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: 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.