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

NCT01091428 | Completed Phase 2 Results FDA Drug

• 3 other identifiers: C140082009-011428-79U1111-1191-6584
• Study Type: interventional
• Target: 191
• Locations: 1 country
• Sites: 4

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).

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

Outcome Measures

Primary Outcomes (7)

• Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) for Alisertib in Combination With Paclitaxel

  The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT). DLT was evaluated according to National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.02 and was defined as any of the following events: 1. Grade 4 neutropenia and thrombocytopenia lasting ≥7 consecutive days; 2. Grade 4 neutropenia with fever and/or infection; 3. Platelet count \<10,000/mm\^3; 4. Grade 3 thrombocytopenia with bleeding; 5. Any other ≥Grade 3 nonhematologic toxicity, with following exceptions: ≥Grade 3 nausea/emesis, ≥Grade 3 diarrhoea, Grade 3 fatigue, Grade 3 nonhematological toxicity that could be controlled to ≤Grade 2 with appropriate treatment; 6. Other alisertib-related nonhematologic toxicities ≥Grade 2 that, in opinion of investigator, required a dose reduction or discontinuation of therapy with alisertib.

  Cycle 1 (Up to 28 days)

• Phase 1: MTD and RP2D for Paclitaxel in Combination With Alisertib

  The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of cycle 1).

  Cycle 1 (Up to 28 days)

• Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

  First dose to 30 days past last dose (Up to 36 Months)

• Phase 1: Number of Participants With Clinically Significant Laboratory Values

  Abnormal clinical laboratory values (serum chemistry, hematology and urinalysis) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention.

  First dose to 30 days past last dose (Up to 36 Months)

• Phase 1: Number of Participants With Clinically Significant Vital Sign Findings

  Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.

  First dose to 30 days past last dose (Up to 36 Months)

• Phase 1: Number of Participants With Hypersensitivity and Neurotoxicity

  Baseline up to Month 36

• Phase 2: Progression-Free Survival (PFS)

  PFS is defined as the time from the date randomization for Phase 2 participants to the date of first documented progressive disease (PD) or death as assessed by the investigator using both RECIST 1.1 criteria and CA-125 criteria. PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease or CA-125 criteria with elevated (\>70 units/mL) levels on 2 occasions. CA 125 progression for participants with normal CA 125 levels is defined as a CA 125 level \> 2 times the upper limit of normal and for participants with elevated values during the trial, is defined as a CA 125 level greater than 2 times the nadir value of CA 125.

  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 (19)

• Phase 1: Combined Best Overall Response Rate (ORR) in Participants With Recurrent Ovarian Cancer or Breast Cancer

  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)

• Cmax: Maximum Observed Concentration for Alisertib in Phase 1

  Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose

• Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1

  Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose

• AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1

  Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose

• AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1

  Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose

Other Outcomes (1)

• Banked Tumor Specimens for Candidate Markers of Response to Alisertib and Taxanes

  Up to 24 Months

Study Arms (4)

Alisertib (Phase 1 - Ovarian cancer)

EXPERIMENTAL

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).

Drug: Alisertib; Drug: Paclitaxel

Alisertib (Phase 1 - Breast cancer)

EXPERIMENTAL

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).

Drug: Alisertib; Drug: Paclitaxel

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

EXPERIMENTAL

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).

Drug: Alisertib; Drug: Paclitaxel

Paclitaxel 80 mg/m^2 (Phase 2)

EXPERIMENTAL

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

Drug: Paclitaxel

Interventions

Alisertib DRUG

Alisertib tablets

Also known as: MLN8237

Alisertib (Phase 1 - Breast cancer); Alisertib (Phase 1 - Ovarian cancer); Alisertib 40 mg BID+Paclitaxel 60 mg/m^2 (Phase 2)

Paclitaxel DRUG

Paclitaxel intravenous infusion

Alisertib (Phase 1 - Breast cancer); Alisertib (Phase 1 - Ovarian cancer); Alisertib 40 mg BID+Paclitaxel 60 mg/m^2 (Phase 2); Paclitaxel 80 mg/m^2 (Phase 2)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (4)

Unknown Facility

The Bronx, New York, United States

Location

Unknown Facility

Philadelphia, Pennsylvania, United States

Location

Unknown Facility

Houston, Texas, United States

Location

Unknown Facility

Seattle, Washington, United States

Location

Related Publications (1)

• 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.

  PMID: 30347019 DERIVED

MeSH Terms

Conditions

Ovarian Neoplasms; Fallopian Tube Neoplasms; Breast Neoplasms

Interventions

MLN 8237; Paclitaxel

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Fallopian Tube Diseases; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Monitor

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 17, 2010
• First Posted: March 24, 2010
• Study Start: April 16, 2010
• Primary Completion: August 12, 2014
• Study Completion: July 19, 2017
• Last Updated: June 4, 2018
• Results First Posted: June 4, 2018

Record last verified: 2018-05

Locations

US (4)