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

Phase 1

Terminated

• Conditions: Advanced Solid Tumors; Ovarian Cancer; Small Cell Lung Cancer
• Interventions: Drug: Alisertib; Drug: Paclitaxel

• Registration Number: NCT02367352
• Lead Sponsor: Millennium Pharmaceuticals, Inc.

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.

Detailed Description

The drug being tested in this study was called alisertib. Alisertib in combination with paclitaxel was tested to find a safe and well-tolerated dose in East Asian participants. The study consisted of 2 parts: a dose escalation phase to determine the maximum tolerated dose (MTD) and define the recommended phase 2 dose (RP2D) of the alisertib plus paclitaxel combination in East Asian participants with advanced solid tumors; the second part is an expansion cohort at the RP2D of the alisertib plus paclitaxel in East Asian participants with either ovarian cancer or small cell lung cancer. This study looked at safety (lab results and side effects) and pharmacokinetic properties (how the drugs move throughout the body).

This open label study enrolled 9 participants. Dose Escalation Phase: Alisertib tablets at a starting dose of 15 mg, orally, twice daily, 3 days on/4 days off for 3 weeks in 28 day cycle in combination with paclitaxel, 60 mg/m\^2 intravenous on days 1, 8, and 15 in 28-day cycles in Cohort 1 escalated to a dose of 25 mg alisertib, orally, twice daily 3 days on/4 days off for 3 weeks in 28 day cycles in Cohort 2. If ≥ 2 participants experience a dose limiting toxicity (DLT) the dose of alisertib decreased to 20 mg. Expansion Cohort: alisertib tablets at the determined RP2D dose orally, twice daily 3 days on/4 days off for 3 weeks in 28 day cycles in combination with paclitaxel, 60 mg/m\^2 intravenous. Treatment was continued until disease progression or unacceptable toxicity.

* Alisertib 15 mg to 25 mg tablets

* Paclitaxel 60 mg/m\^2 intravenous solution

This multi-centre trial was conducted in Japan and Korea. The overall time to participate in this study was up to 24 months.

The study was terminated early because of the sponsor's decision. Enrollment was completed in the dose escalation cohort, but no participants were enrolled in the dose expansion cohort.

Study Timeline

• Study First Submitted: 2015-02-11
• Study First Submitted QC: 2015-02-19
• Study First Posted: 2015-02-20
• Study Start: 2015-03-19
• Primary Completion: 2017-05-23
• Study Completion: 2017-05-23
• Results First Submitted: 2018-04-30
• Results First Submitted QC: 2019-01-29
• Results First Posted: 2019-05-02
• Status Verified: 2019-06
• Last Update Submitted: 2019-06-11
• Last Update Posted: 2019-06-26

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 9

Inclusion Criteria

1. 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.

2. Participants of East Asian ethnicity (eg, Chinese, Japanese, or Korean).

3. 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.

4. 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.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. 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.

7. 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

8. Adequate renal function as defined by:

   • Creatinine clearance ≥ 30 mL/minute (can be calculated using serum creatinine value).

9. No more than 2 previous chemotherapy regimen in the metastatic setting.

10. Female participants who:

    • Are postmenopausal for at least 1 year before the screening visit, OR
    • Are surgically sterile, OR
    • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug
    • Adhere to any treatment-specific pregnancy prevention guidelines for paclitaxel

    Male participants, even if surgically sterilized (ie, status postvasectomy), who:

    • Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug
    • Adhere to any treatment-specific pregnancy prevention guidelines for paclitaxel.

11. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

12. Suitable venous access for the study-required blood sampling, including pharmacokinetics (PK).

13. Ability to swallow tablets.

Exclusion Criteria

1. Participants with carcinomatous meningitis.
2. Participants with symptomatic and/or progressive brain metastases or treatment with brain edema.
3. Known hypersensitivity to Cremophor® EL, paclitaxel, alisertib or their components.
4. Prior treatment with an Aurora A specific-targeted or pan-Aurora-targeted agent, including alisertib in any setting.
5. Prior history of ≥ Grade 2 neurotoxicity or any toxicity requiring discontinuation from taxane chemotherapy that is not resolved to ≤ Grade 1.
6. Participants who received prior weekly taxane-based therapy with early disease progression during or within 1 month of completing therapy (refractory disease).
7. Any comorbid condition or unresolved toxicity that would preclude administration of weekly paclitaxel.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. Treatment with any investigational products within 5 half-lives before the first dose of study drug.
14. 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).
15. Major surgery within 14 days before the first dose of study drug.
16. Infection requiring systemic intravenous (IV) antibiotic therapy within 14 days preceding the first dose of study drug, or other severe infection.
17. Known human immunodeficiency virus (HIV) positive.
18. Ongoing or active hepatitis B or hepatitis C infection. Testing is not required in the absence of clinical findings or suspicion.
19. History of myocardial infarction, unstable symptomatic ischemic heart disease, uncontrolled hypertension despite appropriate medical therapy, any ongoing cardiac arrhythmias of > Grade 2, thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (eg, pericardial effusion or restrictive cardiomyopathy) within 6 months before receiving the first dose of study drug. Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed. Participants with a pacemaker may be enrolled in the study upon discussion with the project clinician.
20. Female participants who are in the lactation period or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day1 before the first dose of study drug.
21. Diagnosed with or treated for another malignancy within 3 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type may be enrolled in the study if they have undergone complete resection and no evidence of active disease is present.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose Expansion Cohort	Alisertib	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.
Cohort 1 (Dose Escalation Phase)	Alisertib	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).
Cohort 1 (Dose Escalation Phase)	Paclitaxel	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).
Cohort 2 (Dose Escalation Phase)	Paclitaxel	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).
Cohort 2 (Dose Escalation Phase)	Alisertib	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).
Dose Expansion Cohort	Paclitaxel	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.

Primary Outcome Measures

Name	Time	Method
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: 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: 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: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	From Day 1 to 30 days after the last dose of study drug (approximately 21 months)	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.
Dose Escalation Phase: Number of Participants With Clinically Significant Laboratory Findings	From Day 1 to 30 days after the last dose of study drug (approximately 21 months)	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.
Dose Escalation Phase: Number of Participants With Clinically Significant Vital Sign Findings	From Day 1 to 30 days after the last dose of study drug (approximately 21 months)	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.
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: 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 Expansion Phase: Number of Participants With Clinically Significant Laboratory Findings	From Day 1 to 30 days after the last dose of study drug	The number of participants with any markedly abnormal standard safety laboratory values will be collected throughout study.
Dose Expansion Phase: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	From Day 1 to 30 days after the last dose of study drug	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.
Dose Expansion Phase: Number of Participants With Clinically Significant Vital Sign Findings	From Day 1 to 30 days after the last dose of study drug	The number of participants with any markedly abnormal vital sign values will be collected throughout study.
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: 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 Outcome Measures

Name	Time	Method
Dose Expansion Phase: Overall Response Rate (ORR)	Day 21 of every other Cycle beginning with Cycle 2 (Up to 12 months)	ORR is defined as the percentage of participants with complete response (CR) and partial response (PR) according to disease response based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.