Alisertib (MLN8237) in Combination With Weekly Paclitaxel in East Asian Patients With Advanced Solid Tumors

NCT02367352 | Terminated Phase 1 Results

• 3 other identifiers: C14022U1111-1164-7696JapicCTI-152845
• Study Type: interventional
• Target: 9
• Locations: 2 countries
• Sites: 3

Brief Summary

The purpose of this study is to evaluate the safety and tolerability and determine the MTD to subsequently define an RP2D of alisertib in combination with weekly paclitaxel in East Asian participants with advanced solid tumors.

Conditions

Advanced Solid Tumors; Ovarian Cancer; Small Cell Lung Cancer

Keywords

Drug therapy; Dose escalation; Dose expansion

Outcome Measures

Primary Outcomes (22)

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

  An AE is considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events. A SAE 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.

  From Day 1 to 30 days after the last dose of study drug (approximately 21 months)

• Dose Escalation Phase: Number of Participants With Clinically Significant Laboratory Findings

  The number of participants with any markedly abnormal standard safety laboratory values including serum chemistry, hematology, and urine analysis will be collected throughout study. Laboratory values assessed by the investigator to be clinically significant were reported as adverse events.

  From Day 1 to 30 days after the last dose of study drug (approximately 21 months)

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

  The number of participants with any markedly abnormal vital sign values (blood pressure, heart rate, and temperature) will be collected throughout study. Vital signs assessed by the investigator to be clinically significant were reported as adverse events.

  From Day 1 to 30 days after the last dose of study drug (approximately 21 months)

• Dose Escalation Phase: Cmax: Maximum Observed Plasma Concentration of Alisertib

  Day 1 and Day 3 predose and at multiple time points (up to 12 hours) post-dose

• Dose Escalation Phase: Tmax: Time to Reach the Maximum Plasma Concentration of Alisertib

  Day 1 and Day 3 predose and at multiple time points (up to 12 hours) post-dose

• Dose Escalation Phase: AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib

  Day 1 and Day 3 predose and at multiple time points (up to 12 hours) post-dose

• Dose Escalation Phase: Cmax: Maximum Observed Plasma Concentration of Paclitaxel

  Day 1 predose and Day 1, 2 and 3 at multiple time points (up to 12 hours) post-dose

• Dose Escalation Phase: Tmax: Time to Reach the Maximum Plasma Concentration of Paclitaxel

  Day 1 predose and Day 1, 2, and 3 at multiple time points (up to 12 hours) post-dose

• Dose Escalation Phase: AUC(0-tlast): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration of Paclitaxel

  Day 1 predose and Day 1, 2, and 3 at multiple time points (up to 12 hours) post-dose

• Dose Escalation Phase: AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Tme 0 to Infinity

  Day 1 predose and Day 1, 2, and 3 at multiple time points (up to 12 hours) post-dose

• Dose Escalation Phase: T½: Terminal Phase Elimination Half-Life of Paclitaxel

  Day 1 predose and Day 1, 2, and 3 at multiple time points (up to 12 hours) post-dose

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

  An AE is considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events. A SAE 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.

  From Day 1 to 30 days after the last dose of study drug

• Dose Expansion Phase: Number of Participants With Clinically Significant Laboratory Findings

  The number of participants with any markedly abnormal standard safety laboratory values will be collected throughout study.

  From Day 1 to 30 days after the last dose of study drug

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

  The number of participants with any markedly abnormal vital sign values will be collected throughout study.

  From Day 1 to 30 days after the last dose of study drug

• Dose Expansion Phase: Cmax: Maximum Observed Plasma Concentration of Alisertib

  Day 1 and Day 3 predose and at multiple time points (up to 12 hours) post-dose

• Dose Expansion Phase: Tmax: Time to Reach the Maximum Plasma Concentration of Alisertib

  Day 1 and Day 3 predose and at multiple time points (up to 12 hours) post-dose

• Dose Expansion Phase: AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib

  Day 1 and Day 3 predose and at multiple time points (up to 12 hours) post-dose

• Dose Expansion Phase: Cmax: Maximum Observed Plasma Concentration of Paclitaxel

  Day 1 predose and Day 1, 2, and 3 at multiple time points (up to 12 hours) post-dose

• Dose Expansion Phase: Tmax: Time to Reach the Maximum Plasma Concentration of Paclitaxel

  Day 1 predose and Day 1, 2, and 3 at multiple time points (up to 12 hours) post-dose

• Dose Expansion Phase: AUC(0-tlast): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration of Paclitaxel

  Day 1 predose and Day 1, 2, and 3 at multiple time points (up to 12 hours) post-dose

• Dose Expansion Phase: AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Paclitaxel

  Day 1 predose and Day 1, 2, and 3 at multiple time points (up to 12 hours) post-dose

• Dose Expansion Phase: T½: Terminal Phase Elimination Half-Life of Paclitaxel

  Day 1 predose and Day 1, 2, and 3 at multiple time points (up to 12 hours) post-dose

Secondary Outcomes (1)

• Dose Expansion Phase: Overall Response Rate (ORR)

  Day 21 of every other Cycle beginning with Cycle 2 (Up to 12 months)

Study Arms (3)

Cohort 1 (Dose Escalation Phase)

EXPERIMENTAL

Alisertib 15 mg, tablet, orally, twice daily, (3 days on/4 days off for 3 weeks) on Days 1 to 3, 8 to 10 and 15 to 17 in 28 day cycles in combination with Paclitaxel 60 mg/m\^2, intravenous (IV), on Days 1, 8, and 15 in a 28-day cycle until disease progression or unacceptable toxicity (Up to 22 Cycles).

Drug: Alisertib; Drug: Paclitaxel

Cohort 2 (Dose Escalation Phase)

EXPERIMENTAL

Alisertib 25 mg, tablet, orally, twice daily, (3 days on/4 days off for 3 weeks) on Days 1 to 3, 8 to 10 and 15 to 17 in 28 day cycles in combination with Paclitaxel 60 mg/m\^2, intravenous (IV), on Days 1, 8, and 15 in 28-day cycle until disease progression or unacceptable toxicity. Dose of alisertib will be de-escalated to 20 mg if ≥ 2 participants experience a dose limiting toxicity (DLT).

Drug: Alisertib; Drug: Paclitaxel

Dose Expansion Cohort

EXPERIMENTAL

Alisertib, MTD/RP2D determined in Dose Escalation Phase, orally, twice daily, (3 days on/4 days off for 3 weeks) on Days 1 to 3, 8 to 10 and 15 to 17 in 28 day cycles in combination with Paclitaxel 60 mg/m\^2, IV on Days 1, 8, and 15 in 28-day cycle until disease progression or unacceptable toxicity.

Drug: Alisertib; Drug: Paclitaxel

Interventions

Alisertib DRUG

Alisertib tablets

Cohort 1 (Dose Escalation Phase); Cohort 2 (Dose Escalation Phase); Dose Expansion Cohort

Paclitaxel DRUG

Paclitaxel intravenous solution

Cohort 1 (Dose Escalation Phase); Cohort 2 (Dose Escalation Phase); Dose Expansion Cohort

Eligibility Criteria

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

You may qualify if:

• Male or female participants 18 years or older (or minimum age of legal consent consistent with local regulations) at the time written study informed consent is obtained.
• Participants of East Asian ethnicity (eg, Chinese, Japanese, or Korean).
• Must have a diagnosis of a solid tumor malignancy (escalation part) or relapsed or refractory ovarian cancer (OC) or small cell lung cancer (SCLC) (expansion part).
• Participants in the expansion cohort must have a pathologically (histology or cytology) confirmed diagnosis of either OC (including recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer) or SCLC, which is measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
• Participants in the expansion cohort must not have received more than 2 prior taxane containing regimens.
• No antineoplastic therapy (eg, drugs, biologicals, monoclonal antibodies, etc) or radiotherapy within the 3 weeks before enrollment (14 days for regimens with recovery expected within 7 to 14 days). The participant must have recovered (ie, ≤ Grade 1 toxicity or participant's baseline status, except alopecia) from all treatment-related toxicities.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate bone marrow function as defined by:
• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 (without need for growth factor support).
• Platelet count ≥ 100,000 cells/mm3 (without need for transfusion or growth factor support).
• Hemoglobin level ≥ 9 g/dL.
• Adequate liver function as defined by:
• Bilirubin \< 1.5 times the upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN if due to liver metastases)
• Serum albumin equal to or greater than the lower limit of normal

You may not qualify if:

• Participants with carcinomatous meningitis.
• Participants with symptomatic and/or progressive brain metastases or treatment with brain edema.
• Known hypersensitivity to Cremophor® EL, paclitaxel, alisertib or their components.
• Prior treatment with an Aurora A specific-targeted or pan-Aurora-targeted agent, including alisertib in any setting.
• Prior history of ≥ Grade 2 neurotoxicity or any toxicity requiring discontinuation from taxane chemotherapy that is not resolved to ≤ Grade 1.
• Participants who received prior weekly taxane-based therapy with early disease progression during or within 1 month of completing therapy (refractory disease).
• Any comorbid condition or unresolved toxicity that would preclude administration of weekly paclitaxel.
• Systemic treatment with moderate or strong CYP3A inhibitors must be discontinued at least 14 days before the first dose of alisertib, and the use of these agents is not permitted during the study.
• Known gastrointestinal (GI) abnormality (including recurrent nausea or vomiting) or GI procedure that could interfere with or modify the oral intake, absorption, or tolerance of alisertib.
• Participants requiring treatment with clinically significant enzyme inducers, such as the enzyme-inducing antiepileptic drugs phenytoin, carbamazepine, phenobarbital, oxcarbazepine, primidone, rifampin, rifabutin, rifapentine, or St. John's wort within 14 days before the first dose of alisertib or requiring the use of these medications during the study.
• Requirement for administration of proton pump inhibitor (PPI), H2 antagonist (premedication for paclitaxel allowed), or pancreatic enzymes. Use of any PPI in either continued or intermittent use will be prohibited during the conduct of the study and participants must discontinue any use of PPI within 4 days before the first dose of alisertib.
• Life-threatening or severe central nervous system (CNS), pulmonary, renal, or hepatic disease unrelated to cancer, or any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
• Treatment with any investigational products within 5 half-lives before the first dose of study drug.
• Treatment with fully human or chimeric monoclonal antibodies within 42 days before the first dose of study drug (21 days if clear evidence of progression).
• Major surgery within 14 days before the first dose of study drug.

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (3)

Unknown Facility

Chiba, Japan

Location

Unknown Facility

Shizuoka, Japan

Location

Unknown Facility

Seoul, South Korea

Location

MeSH Terms

Conditions

Ovarian Neoplasms; Small Cell Lung Carcinoma

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; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract 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 Director Clinical Science

  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 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 11, 2015
• First Posted: February 20, 2015
• Study Start: March 19, 2015
• Primary Completion: May 23, 2017
• Study Completion: May 23, 2017
• Last Updated: June 26, 2019
• Results First Posted: May 2, 2019

Record last verified: 2019-06

Locations

JP (2); KR (1)