Phase I Study of MLN0128 and MLN8237 in Patients With Advanced Solid Tumors and Metastatic Triple-negative Breast Cancer

NCT02719691 | Completed Phase 1 Results DMC

• 1 other identifier: 15-1135.cc
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase Ib study designed to evaluate the safety and toxicity of the combination of Alisertib and MLN0128 in patients with advanced solid tumors with an expansion cohort in patients with previously treated metastatic TNBC.

Conditions

Metastatic Breast Cancer; Solid Tumors

Keywords

MLN0128; Dual TORC1/2 Inhibitor; MLN8237; Aurora A inhibitor; Alisertib; Triple-Negative Breast Cancer

Outcome Measures

Primary Outcomes (1)

• The Maximum Tolerated Dose (MTD) in the Combination of MLN0128 and Alisertib in Patients With Advanced Solid Tumors Measured by Treatment Adverse Events as Assessed by the CTCAE v4.03

  The maximum tolerated dose (MTD) will be defined as the highest dose level evaluated in which 0 or 1 patient out of 6 patients experiences dose limiting toxicity (DLT) in the combination of MLN0128 and Alisertib. Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03.

  Up to 28 days

Secondary Outcomes (1)

• The Safety Profile and Tolerability of the Combination of MLN0128 and Alisertib in Adult Patients With Advanced Solid Tumors.

  At least 30 days after the last dose of MLN0128 or alisertib

Study Arms (7)

Dose level 1: Alisertib 30mg/MLNO128 1mg

EXPERIMENTAL

This group will receive a Dose-Escalation: Combination of MLN0128 and Alisertib using a standard 3 + 3 design. The starting dose of Alisertib is 30 mg given PO twice daily (BID) Days 1-7 repeat every 21 days. The starting dose for MLN0128 is 1 mg given by mouth (PO) once daily with continuous dosing. Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study. MLN0128: Participants will receive MLN0128 in the dose-escalation and the dose-expansion part of the study.

Drug: Alisertib; Drug: MLN0128

Dose Level 2: Alisertib 30mg/MLNO128 2 mg

EXPERIMENTAL

This group will receive a Dose-Escalation: Combination of MLN0128 and Alisertib using a standard 3 + 3 design. The starting dose of Alisertib is 30 mg given PO twice daily (BID) Days 1-7 repeat every 21 days. The starting dose for MLN0128 is 2 mg given by mouth (PO) once daily with continuous dosing. Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.

Drug: Alisertib; Drug: MLN0128

Dose Level 3: Alisertib 40 mg/MLNO128 2 mg

EXPERIMENTAL

This group will receive a Dose-Escalation: Combination of MLN0128 and Alisertib using a standard 3 + 3 design. The starting dose of Alisertib is 40 mg given PO twice daily (BID) Days 1-7 repeat every 21 days. The starting dose for MLN0128 is 1 mg given by mouth (PO) once daily with continuous dosing. Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.

Drug: Alisertib; Drug: MLN0128

Dose Level 4: Alisertib 40 mg/MLN0128 3 mg

EXPERIMENTAL

This group will receive a Dose-Escalation: Combination of MLN0128 and Alisertib using a standard 3 + 3 design. The starting dose of Alisertib is 40 mg given PO twice daily (BID) Days 1-7 repeat every 21 days. The starting dose for MLN0128 is 3 mg given by mouth (PO) once daily with continuous dosing. Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.

Drug: Alisertib; Drug: MLN0128

Dose-Expansion of Alisertib and Dose-Expansion of MLN0128: Group 1

EXPERIMENTAL

This group will receive a Dose-Expansion of Alisertib and Dose-Expansion of MLN0128. In cycle 1, single agent Alisertib will be administered at the MTD on days 1-7 and MLN0128 will be administered on days 8-21. In cycle 2 and beyond, dosing with both agents will begin on day 1, with Alisertib administered days 1-7 and MLN0128 administered days 1-21. Pancreatic Cancer Cohort: This group will receive a Dose-Expansion of Alisertib and Dose-Expansion of MLN0128. On each cycle, Alisertib will be administered on days 1-7, while MLN0128 will be administered continuously on days 1-21.

Drug: Alisertib; Drug: MLN0128

Dose-Expansion of Alisertib and Dose-Expansion of MLN0128: Group 2

EXPERIMENTAL

This group will receive a Dose-Expansion of Alisertib and Dose-Expansion of MLN0128. In cycle 1, MLN0128 will be administered at the MTD days 1-28 and Alisertib will be administered at the MTD on days 8-15. In cycle 2 and beyond, dosing with both agents will begin on day 1, with Alisertib administered days 1-7 and MLN0128 administered days 1-21.

Drug: Alisertib; Drug: MLN0128

Pancreatic Cohort

EXPERIMENTAL

This group will receive a Dose-Expansion of Alisertib and Dose-Expansion of MLN0128. On each cycle, Alisertib will be administered on days 1-7, while MLN0128 will be administered continuously on days 1-21.

Drug: Alisertib; Drug: MLN0128

Interventions

Alisertib DRUG

Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.

Also known as: Dual TORC1/2 Inhibitor

Dose Level 2: Alisertib 30mg/MLNO128 2 mg; Dose Level 3: Alisertib 40 mg/MLNO128 2 mg; Dose Level 4: Alisertib 40 mg/MLN0128 3 mg; Dose level 1: Alisertib 30mg/MLNO128 1mg; Dose-Expansion of Alisertib and Dose-Expansion of MLN0128: Group 1; Dose-Expansion of Alisertib and Dose-Expansion of MLN0128: Group 2; Pancreatic Cohort

MLN0128 DRUG

Participants will receive MLN0128 in the dose-escalation and the dose-expansion part of the study.

Also known as: MLN8237 (Aurora A inhibitor)

Dose Level 2: Alisertib 30mg/MLNO128 2 mg; Dose Level 3: Alisertib 40 mg/MLNO128 2 mg; Dose Level 4: Alisertib 40 mg/MLN0128 3 mg; Dose level 1: Alisertib 30mg/MLNO128 1mg; Dose-Expansion of Alisertib and Dose-Expansion of MLN0128: Group 1; Dose-Expansion of Alisertib and Dose-Expansion of MLN0128: Group 2; Pancreatic Cohort

Eligibility Criteria

• Age: 18 Years - 101 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients 18 years or older.
• Dose Escalation Cohort: Patients must have a diagnosis of a histologically confirmed solid tumor that is incurable and refractory to standard therapy or for which no standard therapy exists.
• Dose Expansion Cohort Group 1 and 2: Patients must have a diagnosis of histologically confirmed metastatic TNBC defined as negative for estrogen receptor, progesterone receptor and HER2. Patients must have received either adjuvant or first line chemotherapy for metastatic disease. Negative for Estrogen and Progesterone Receptor includes the following:
• Local Pathology report classifies them as negative
• Allred Score of 2 or below
• \<1% positive staining Subjects with solid tumor types other than TNBC may also be enrolled after discussion with the Sponsor. These subjects must have a diagnosis of a histologically confirmed solid tumor that is incurable and refractory to standard therapy or for which no standard therapy exists.
• Pancreatic Cancer Cohort: Patients must have a diagnosis of locally advanced or metastatic pancreatic adenocarcinoma previously treated with or not a candidate for standard of care systemic therapy. Dose Expansion Cohort Group 1 and 2: At least one tumor lesion amenable to repeat core needle biopsy or punch biopsy without unacceptable risk of a major procedural complication.
• Dose Expansion Cohort Group 1 and 2: At least one tumor lesion amenable to repeat core needle biopsy or punch biopsy without unacceptable risk of a major procedural complication.
• Eastern Cooperative Oncology Group (ECOG) performance status \< 1 (See Appendix 1)
• Three weeks or 5 half-lives (whichever is shorter) from previous systemic anticancer therapy; at least 4 weeks from major surgery and recovered; at least 2 weeks from palliative radiation and recovered. No more than 450 mg/m2 cumulative dose of doxorubicin or equivalent anthracycline dose is allowed.
• All acute treatment-related toxicities from prior therapy must have resolved to Grade \< 1 prior to study entry excluding alopecia.
• For women:
• Postmenopausal for at least 1 year before the screening visit, OR
• 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 90 days after the last dose of study drug OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (Periodic abstinence \[e.g, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.

You may not qualify if:

• Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the patient's participation in the study.
• Known human immunodeficiency virus infection.
• Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is considered to be over 25%.
• Known history of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease; requirement for supplemental oxygen.
• Systemic infection requiring IV antibiotic therapy within 14 days preceding the first dose of study drug, or other severe infection.
• Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
• Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• Breast feeding or pregnant.
• Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of MLN0128. In addition, patients with enteric stomata are also excluded.
• Treatment with any investigational products within 3 weeks before the first dose of study drug.
• History of any of the following within the last 6 months before administration of the first dose of the drug:
• Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures
• Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures
• Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia)

Sponsors & Collaborators

• University of Colorado, Denver: lead

Study Sites (1)

University of Colorado Cancer Center

Aurora, Colorado, 80045, United States

Location

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Interventions

MLN 8237; sapanisertib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Jennifer Diamond, MD
• Organization: University of Colorado

jennifer.diamond@cuanschutz.edu

303-724-5499

Study Officials

• Jennifer R. Diamond, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 21, 2016
• First Posted: March 25, 2016
• Study Start: May 13, 2016
• Primary Completion: March 18, 2020
• Study Completion: March 18, 2020
• Last Updated: July 25, 2022
• Results First Posted: January 19, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)