A Safety, Tolerability, and Pharmacokinetics Study of MLN0128 as a Single Agent and in Combination With Paclitaxel in Adults With Advanced Nonhematologic Malignancies

NCT02412722 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: MLN0128-1004U1111-1161-4803
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 5

Brief Summary

The purposes of this study are to evaluate the safety and tolerability of sapanisertib (MLN0128) milled active pharmaceutical ingredient (API) capsules administered both as a single agent and in combination with paclitaxel, to characterize the effect of a high-fat meal on the pharmacokinetics (PK) of sapanisertib milled API capsules, and to characterize the PK of sapanisertib milled API capsules when administered on an empty stomach approximately 24 hours after paclitaxel infusion.

Conditions

Non-hematologic Malignancy

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (7)

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

  An 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. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is defined as an untoward medical occurrence, significant hazard, contraindication, side effect or precaution that at any dose: 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, Cycle 1 through 30 days after the last dose of study drug (up to 15 months)

• Geometric Mean Ratio of Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled Active Pharmaceutical Ingredient (API) Capsules Under Fasted and Fed Conditions

  Days 3 and 5 predose and at multiple time points (up to 24 hours) post-dose

• Geometric Mean Ratio of AUC(0-last): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration of Sapanisertib Milled API Capsules Under Fasted and Fed Conditions

  Days 3 and 5 predose and at multiple time points (up to 24 hours) post-dose

• Geometric Mean Ratio of AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib Milled API Capsules Under Fasted and Fed Conditions

  Days 3 and 5 predose and at multiple time points (up to 24 hours) post-dose

• Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion

  Cycle 1, Day 2 pre-dose and at multiple time points (up to 8 hours) post-dose

• Tmax: Time to Reach the Maximum Plasma Concentration of Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion

  Cycle 1, Day 2 pre-dose and at multiple time points (up to 8 hours) post-dose

• AUC(0-8): Area Under the Plasma Concentration Curve From Time Zero to 8 Hours Post-dose for Sapanisertib Milled API Capsules Under Fasted Conditions Approximately 24 Hours After Paclitaxel Infusion

  Cycle 1, Day 2 pre-dose and at multiple time points (up to 8 hours) post-dose

Secondary Outcomes (7)

• Geometric Mean Ratio of Cmax: Maximum Observed Plasma Concentration of Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions

  Days 1 and 3 pre-dose and at multiple time points (up to 24 hours) post-dose

• Geometric Mean Ratio of AUC(0-last): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions

  Days 1 and 3 pre-dose and at multiple time points (up to 24 hours) post-dose

• AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Sapanisertib Milled Versus Unmilled API Capsules Under Fasted Conditions

  Days 1 and 3 pre-dose and at multiple time points (up to 24 hours) post-dose

• Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST)

  Baseline then every 2 cycles beginning at Cycle 3, Day 1, until disease progression, death or end of study (Up to 14 months)

• Progression Free Survival (PFS)

  Baseline then every 2 cycles beginning at Cycle 3, Day 1, until disease progression, death or end of study (Up to 14 months)

Study Arms (6)

Single-Agent QD Arm: Sapanisertib 3 mg

EXPERIMENTAL

Following Pharmacokinetic (PK) - Run in Period, sapanisertib 3 mg milled capsules, orally, once, daily in a 28-day Cycle, under fasted conditions, starting from Cycle 2 for up to 9 cycles. The dose of sapanisertib was modified based on safety and tolerability during each 28-day cycle.

Drug: Sapanisertib

Single-Agent QD Arm: Sapanisertib 4 mg

EXPERIMENTAL

Following PK Run-In Period, sapanisertib 4 mg milled capsules, orally, once, daily in a 28-day Cycle, under fasted conditions, for up to 13 cycles.

Drug: Sapanisertib

Combination Arm: Sapanisertib 4 mg + Paclitaxel 80 mg/m^2

EXPERIMENTAL

Sapanisertib 4 mg milled capsules, orally, once, for 3 consecutive days following each paclitaxel administration (Days 2-4, 9-11, 16-18, and 23-25) in a 28-day Cycle, under fasted conditions, for up to 12 cycles, and paclitaxel 80 mg/m\^2, intravenously (IV), on Days 1, 8, and 15 in 28-day Cycle, for up to 6 cycles.

Drug: Sapanisertib; Drug: Paclitaxel

Combination Arm: Sapanisertib 6 mg + Paclitaxel 80 mg/m^2

EXPERIMENTAL

Sapanisertib 6 mg milled capsules, orally, once, for 3 consecutive days following each paclitaxel administration (Days 2-4, 9-11, 16-18, and 23-25) in a 28-day Cycle, under fasted conditions, for up to 9 cycles, and paclitaxel 80 mg/m\^2, IV, on Days 1, 8, and 15 in 28-day Cycle, for up to 9 cycles. The dose of sapanisertib was modified based on safety and tolerability during each 28-day cycle.

Drug: Sapanisertib; Drug: Paclitaxel

Single-Agent QW Arm: Sapanisertib 20 mg

EXPERIMENTAL

Sapanisertib 20 mg, capsules milled API, QW in a 28-day Cycle, for up to 6 cycles.

Drug: Sapanisertib

Single-Agent QW Arm: Sapanisertib 30 mg

EXPERIMENTAL

Sapanisertib 30 mg, capsules, milled API, QW in a 28-day Cycle, for up to 10 cycles.

Drug: Sapanisertib

Interventions

Sapanisertib DRUG

Sapanisertib capsules

Combination Arm: Sapanisertib 4 mg + Paclitaxel 80 mg/m^2; Combination Arm: Sapanisertib 6 mg + Paclitaxel 80 mg/m^2; Single-Agent QD Arm: Sapanisertib 3 mg; Single-Agent QD Arm: Sapanisertib 4 mg; Single-Agent QW Arm: Sapanisertib 20 mg; Single-Agent QW Arm: Sapanisertib 30 mg

Paclitaxel DRUG

Paclitaxel injection

Combination Arm: Sapanisertib 4 mg + Paclitaxel 80 mg/m^2; Combination Arm: Sapanisertib 6 mg + Paclitaxel 80 mg/m^2

Eligibility Criteria

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

You may qualify if:

• Age is ≥ 18 years, including males and females.
• Has Advanced nonhematologic malignancies, with the exception of primary brain tumor, and have failed or are not eligible for standard of care therapy. History of brain metastasis may be allowed if all the following criteria are met: brain metastases have been treated, there is no evidence of progression or hemorrhage after treatment, dexamethasone discontinued for ≥ 4 weeks before first study drug administration, and there is no ongoing requirement for dexamethasone or anti-epileptic drugs.
• Has received not more than 4 prior lines of systemic cytotoxic chemotherapy for advanced or metastatic disease.
• Has Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1.
• Has adequate organ function, including the following:
• Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L; platelet count ≥ 100 x 10\^9/L; and hemoglobin ≥ 9 g/dL without transfusion in the last 2 weeks
• Hepatic: total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN), transaminases (aspartate aminotransferase \[AST\]/serum glutamic oxaloacetic transaminase \[SGOT\] and alanine aminotransferase \[ALT\]/serum glutamic pyruvic transaminase \[SGPT\]) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present)
• Renal: normal serum creatinine or calculated creatinine clearance ≥ 60 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12- or 24-hour)
• Metabolic: fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL
• Has left ventricular ejection fraction (LVEF) within 5 absolute percentage points of institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks before first study drug administration (ie, if the institutional normal is 50%, participant's LVEF may be as low as 45% to be eligible for the study).
• Is a 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 form 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 participant. (Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.)

You may not qualify if:

• Has a diagnosis of primary brain tumor.
• Has untreated brain metastasis or history of leptomeningeal disease or spinal cord compression.
• Has failed to recover from the reversible effects of prior anticancer therapies with the exception of alopecia, and after-effects associated with prior tyrosine kinase inhibitor therapy, such as hair depigmentation, hypothyroidism, and/or splinter hemorrhage.
• Has received prior cancer therapy or other investigational therapy within 2 weeks before the first administration of study drug. For prior therapies with a half-life longer than 3 days, the interval must be at least 28 days before the first administration of study drug, and the participant must have documented disease progression.
• Has initiation of hematopoietic growth factors within 1 week before the first administration of any study drug; participants already receiving hematopoietic growth factors on a chronic basis for ≥ 4 weeks are eligible.
• Has chronic systemic corticosteroid (except inhalers) use within 1 week before the first administration of study drug. Premedication with dexamethasone before paclitaxel administration in this study is allowed.
• Has manifestations of malabsorption due to prior gastrointestinal surgery, gastrointestinal disease, or for an unknown reason that may alter the absorption of MLN0128.
• Has poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) \> 7%; participants with a history of transient glucose intolerance due to corticosteroid administration are allowed if all other eligibility criteria are met.
• Has other clinically significant comorbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the participant's participation in the study.
• Has a known human immunodeficiency virus infection.
• Is pregnant (positive serum or urine pregnancy test) or breastfeeding.
• Has any history of unstable angina, myocardial infarction, New York Heart Association Class III or IV heart failure, and/or pulmonary hypertension.
• Has significant active cardiovascular disease including:
• Uncontrolled high blood pressure (ie, systolic blood pressure \> 180 mmHg, diastolic blood pressure \> 95 mmHg)
• Grade 3 or higher valvular disease

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (5)

Unknown Facility

Scottsdale, Arizona, United States

Location

Unknown Facility

Sarasota, Florida, United States

Location

Unknown Facility

Oklahoma City, Oklahoma, United States

Location

Unknown Facility

Germantown, Tennessee, United States

Location

Unknown Facility

Nashville, Tennessee, United States

Location

Related Publications (2)

• Chopra M. Annual Congress of the European Society for Medical Oncology (ESMO): Copenhagen, Denmark; 7-11 October 2016. Target Oncol. 2016 Dec;11(6):705-709. doi: 10.1007/s11523-016-0464-3. No abstract available.

  PMID: 27812901 BACKGROUND

• Moore KN, Bauer TM, Falchook GS, Chowdhury S, Patel C, Neuwirth R, Enke A, Zohren F, Patel MR. Phase I study of the investigational oral mTORC1/2 inhibitor sapanisertib (TAK-228): tolerability and food effects of a milled formulation in patients with advanced solid tumours. ESMO Open. 2018 Feb 1;3(2):e000291. doi: 10.1136/esmoopen-2017-000291. eCollection 2018.

  PMID: 29464110 DERIVED

MeSH Terms

Interventions

sapanisertib; Paclitaxel

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

  Takeda

  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: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 10, 2015
• First Posted: April 9, 2015
• Study Start: March 26, 2015
• Primary Completion: May 31, 2018
• Study Completion: May 31, 2018
• Last Updated: February 28, 2020
• Results First Posted: February 28, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will share

Locations

US (5)