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A Phase 1 Study of Alisertib Participants With Advanced Solid Tumors Including Castration-Resistant Prostate Cancer Receiving a Standard Docetaxel Regimen

Primary Purpose

Advanced Solid Tumors, Adenocarcinoma of the Prostate

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Alisertib

Docetaxel

About this trial

This is an interventional treatment trial for Advanced Solid Tumors

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

18 years or older
Histologically or cytologically confirmed advanced tumors and candidates for docetaxel treatment
Measurable or evaluable disease is required. Participants must have clinical evidence of progressive disease or persistent disease
Participants with castration-resistant prostate cancer (CRPC) are required to have
- Pathologically confirmed adenocarcinoma of the prostate
- Evidence of metastatic disease on bone scan or other imaging. Participants with prostate-specific antigen (PSA) elevation as the only manifestation of disease are not eligible.
- Progressive disease after at least 1 hormonal treatment with documented testosterone levels less than 50 ng/dl
- Concurrent use of an agent for testosterone suppression (e.g., luteinizing hormone-releasing hormone [LHRH] agonist) is required if the participants has not been surgically castrated
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Recovered to less than or equal to Grade 1 toxicity (CTCAE), to participant's baseline status (except alopecia) or deemed irreversible from the effects of prior cancer therapy and must have evidence of progressive or persistent disease
Adequate bone marrow, liver and renal function
Any use of opiates must be stable for at least 2 weeks prior to study entry
Female participants who are postmenopausal for at least 1 year OR are surgically sterile OR if of childbearing potential, agree to practice 2 effective methods of contraception at the same time
Male participants who agree to practice effective barrier contraception during the entire study and through 6 months after the last dose of study drug OR agree to abstain from heterosexual intercourse
Voluntary written consent
Willing to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures
Suitable venous access for blood sampling

Exclusion Criteria:

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

Female participants who are lactating or pregnant
Antineoplastic therapy or any experimental therapy within 21 days before the first dose of alisertib
Prior or current investigational therapies within 4 weeks before the first dose of MLN8237
Concurrent investigational treatment of treatment with any investigational products within 28 days before the first dose of alisertib
Radiotherapy to greater than 40% of bone marrow or any radiotherapy (except localized, small field radiation) within 4 weeks prior to enrollment, unless reviewed and approved by the medical monitor
Nitrosoureas or mitomycin-C within 6 weeks before the first dose of alisertib.
Autologous stem cell transplant within 3 months before the first dose of alisetib, or prior allogeneic stem cell transplant at any time.
Use of enzyme-inducing antiepileptic drugs such as phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin, rifapentine or St. John's wort within 14 days prior to the first dose of alisertib
For CRPC participants:
- Radiotherapy or antiandrogen therapy for prostate cancer within 4 weeks prior to enrollment
- Prior treatment with antineoplastic chemotherapy or radioisotopes for advanced prostate cancer
- Use of products known to affect PSA levels within 4 weeks of enrollment
Major surgery within 4 weeks of study enrollment
Uncontrolled high blood pressure
Participants with abnormal gastric or bowel function or who require continuous treatment with antacids or proton pump inhibitors
Participants receiving chronic steroid therapy other than the following: low dose steroid for the control of nausea and vomiting, topical steroid, inhaled steroid or use of dexamethasone
Known severe hypersensitivity to docetaxel or other drugs formulated in polysorbate 80
Comorbid condition or unresolved toxicity that would preclude administration of docetaxel
Prior history of Grade 2 or greater neurotoxicity or any toxicity that has not resolved to Grade 1 or below
Symptomatic brain or other CNS metastasis
Diagnosis or treatment of another malignancy within 2 years preceding first dose of study drug except nonmelanoma skin cancer or in situ malignancy completely resected
Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C
Participants requiring full systemic anticoagulation
Prior allogeneic bone marrow or other organ transplant
Active infection requiring systemic therapy within 14 days preceding first dose, or other serious infection
History of hemorrhagic or thrombotic cerebrovascular event in the past 12 months
Serious medical or psychiatric illness that could interfere with protocol completion
Inability to swallow oral medication
Prior treatment with more than 3 myelosuppressive cytotoxic chemotherapy regimens
Prior treatment with more than 1 prior taxane-containing regimen

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Alisertib + Docetaxel

Arm Description

Alisertib in escalating dose (10-40 mg), enteric-coated tablets (ECT), orally, twice daily for 7 days followed by 14-day rest period in Cycle 1, 3 and onwards (21-day cycle) and orally twice daily from Day 3 to Day 7 followed by 14 day rest period in Cycle 2 along with docetaxel 60-75 mg/m^2, intravenous (IV) infusion on Day 1 of each cycle for maximum of 12 months, or until the occurrence of progressive disease (PD), unmanageable adverse events (AEs) or withdrawal of consent. The starting alisertib dose is 10 mg, orally, twice daily (total 20 mg/day).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Cmax: Maximum Observed Plasma Concentration for Docetaxel

AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel

AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel

Terminal Phase Elimination Half-life (T1/2) for Docetaxel

Cmax: Maximum Observed Plasma Concentration for Alisertib

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib

AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Day 7 Over the Dosing Interval for Alisertib

Overall Response Rate (ORR) Assessed for Overall Participant Population

ORR is defined as percentage of participants who achieved complete response (CR) or partial response (PR) as assessed by response evaluation criteria in solid tumors (RECIST) v 1.1. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as ≥30% decrease in sum of longest diameter (LD) of target lesions in reference to Baseline. RECIST-Evaluable Population is subset of safety population who had measurable disease by RECIST v 1.1 at baseline and had at least 1 post baseline response. prostate specific antigen (PSA)-Evaluable Population is subset of the safety population who had a baseline PSA reference value (>5 ng/mL) and at least 12 weeks post-baseline PSA assessment for participants with no decline from baseline, or PSA progression within 12 weeks of treatment for participants with PSA decline from baseline.

Overall Response Rate for Prostate Cancer Participants

ORR is defined as percentage of participants who achieved CR or PR as assessed by either RECIST v 1.1 or PSA response by prostate cancer working group 2 (PCWG2) criteria. According to RECIST v 1.1, CR: disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: ≥30% decrease in sum of LD of target lesions in reference to Baseline sum LD. PSA response by PCWG2 is defined as PSA at least 50% decrease in PSA value from baseline for 2 consecutive evaluations. PCWG2 defines PSA progression as the date that a 25% or greater increase and an absolute increase of 2 ng/mL or more from the nadir is documented, which is confirmed by a second value obtained 3 or more weeks later.

Best Overall Response Rate Assessed by RECIST Criteria

Best response rate is defined as the percentage of participants with CR, PR, CR+PR, stable disease (SD) and progressive disease (PD) as assessed by RECIST criteria 1.1 for target lesions and assessed by CT, PET or MRI. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

Best Overall Response Rate Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria

Best Response Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria PSA response is defined as at least 50% decrease in PSA value from baseline for 2 consecutive evaluations.

Duration of Response

Duration of response is defined as the time from the date of first documentation of a response to the date of first documented progressive disease (PD), or censored at last SD or better.

Duration of Stable Disease (SD)

Duration of SD is defined as the time from first dose to first PD, or censored at last SD or better.

Full Information

NCT ID

NCT01094288

First Posted

March 17, 2010

Last Updated

October 4, 2018

Sponsor

Millennium Pharmaceuticals, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT01094288

Brief Title

A Phase 1 Study of Alisertib Participants With Advanced Solid Tumors Including Castration-Resistant Prostate Cancer Receiving a Standard Docetaxel Regimen

Official Title

A Phase 1 Study of MLN8237, an Aurora A Kinase Inhibitor, in Patients With Advanced Solid Tumors Including Castration-Resistant Prostate Cancer Receiving a Standard Docetaxel Regimen

Study Type

Interventional

2. Study Status

Record Verification Date

October 2018

Overall Recruitment Status

Completed

Study Start Date

August 17, 2010 (Actual)

Primary Completion Date

February 28, 2014 (Actual)

Study Completion Date

January 4, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Millennium Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

The purpose of this study is to evaluate the safety and tolerability of alisertib in combination with docetaxel as a treatment for participants with advanced solid tumors, including castration-resistant prostate cancer, who were deemed by the investigator to be medically appropriate candidates for docetaxel therapy.

Detailed Description

The drug being tested in this study is called alisertib (MLN8237). Alisertib is being tested to treat people who have advanced solid tumors including castration-resistant prostate cancer. The study enrolled approximately 41 patients. Participants were enrolled to receive: • Alisertib 10-40 mg + docetaxel 60-75 mg/m^2 All participants will receive alisertib (ECT) in dose escalating cohorts, orally, twice daily for 7 days followed by 14-day rest period in Cycle 1, 3 and onwards (21-day cycle) and orally twice daily from Day 3 to Day 7 followed by 14 day rest period in Cycle 2 [dose held for pharmacokinetic (PK) collection] along with docetaxel 75 mg/m^2, intravenous (IV) infusion on Day 1 of each cycle for maximum of 12 months, or until the occurrence of progressive disease (PD), unmanageable AEs or withdrawal of consent. This multi-center trial is conducted in United States. The overall time to participate in this study was until there is evidence of disease progression or unacceptable treatment-related toxicity. Participants made multiple visits to the clinic, and were contacted every 12 weeks for up to 25.8 months after last dose of study drug for a follow-up assessment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Advanced Solid Tumors, Adenocarcinoma of the Prostate

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

41 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Alisertib + Docetaxel

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Alisertib

Other Intervention Name(s)

MLN8237

Intervention Description

Alisertib ECT

Intervention Type

Drug

Intervention Name(s)

Docetaxel

Intervention Description

Docetaxel IV infusion

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Description

Time Frame

From enrollment through 30 days after the last dose of study drug (approximately up to 77 months)

Secondary Outcome Measure Information:

Title

Cmax: Maximum Observed Plasma Concentration for Docetaxel

Time Frame

Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2

Title

AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel

Time Frame

Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2

Title

AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel

Time Frame

Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2

Title

Terminal Phase Elimination Half-life (T1/2) for Docetaxel

Time Frame

Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2

Title

Cmax: Maximum Observed Plasma Concentration for Alisertib

Time Frame

Prior to dosing on Day 1 and Day 5 or 7 and at multiple time points (up to 12 hours) post-dose in Cycle 1

Title

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib

Time Frame

Prior to dosing on Day 1 and Day 5 or 7 and at multiple time points (up to 12 hours) post-dose in Cycle 1

Title

AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Day 7 Over the Dosing Interval for Alisertib

Time Frame

Prior to dosing on Day 1 and Day 5 or 7 and at multiple time points (up to 12 hours) post-dose in Cycle 1

Title

Overall Response Rate (ORR) Assessed for Overall Participant Population

Description

Time Frame