Evaluation of the Safety and Tolerability of TAK-228 With TAK-117 and Paclitaxel in Advanced Solid Tumors

NCT03154294 | Completed Phase 1 Results FDA Drug

• 1 other identifier: X31025
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, cohort study to determine the feasibility and tolerability of the combination of TAK-228 and TAK-117 given on days 2-4, 9-11, 16-18, and 23-25 with paclitaxel on days 1, 8, and 15 for one 28-day cycle in patients with advanced solid tumors.

Conditions

Advanced Solid Tumor

Outcome Measures

Primary Outcomes (1)

• Number of Patients Who Developed Does-limiting Toxicity (DLT)

  DLT is defined as any death not clearly due to underlying disease or extraneous causes; critical liver injury by Hy's Law; grade 3 or higher toxicity (with certain exceptions); inability to administer at least 75% of planned doses of TAK-228 within Cycle 1, due to study drug-related toxicity and any other clinically significant occurrence that the investigator and sponsor agree would place patients at an undue safety risk.

  30 days

Secondary Outcomes (4)

• Number of Patients With Beneficial Clinical Response

  27 months

• Number of Patients With Tumor Objective Response

  27 months

• Progression Free Survival (in Month)

  27 months

• Overall Survival

  Baseline until date of death, assessed up to 43 months

Other Outcomes (1)

• Number of Patients With MTOR and PI3K Alterations Who Had Clinical Favorable Responses.

  27 months

Study Arms (5)

Cohort 1

EXPERIMENTAL

Paclitaxel 60mg/m2 Day 1, Day 8, Day 15 TAK-228 2mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 TAK-117 100mg Days 2-4, Days 9-11, Days 16-18, Days 23-25

Drug: paclitaxel; Drug: TAK-228; Drug: TAK-117

Cohort 2

EXPERIMENTAL

Paclitaxel 60mg/m2 Day 1, Day 8, Day 15 TAK-228 2mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 TAK-117 200mg Days 2-4, Days 9-11, Days 16-18, Days 23-25

Drug: paclitaxel; Drug: TAK-228; Drug: TAK-117

Cohort 3

EXPERIMENTAL

Paclitaxel 80mg/m2 Day 1, Day 8, Day 15 TAK-228 2mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 TAK-117 200mg Days 2-4, Days 9-11, Days 16-18, Days 23-25

Drug: paclitaxel; Drug: TAK-228; Drug: TAK-117

Cohort 4

EXPERIMENTAL

Paclitaxel 80mg/m Day 1, Day 8, Day 15 TAK-228 3mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 TAK-117 200mg Days 2-4, Days 9-11, Days 16-18, Days 23-25

Drug: paclitaxel; Drug: TAK-228; Drug: TAK-117

Cohort 5

EXPERIMENTAL

Paclitaxel 80mg/m2 Day 1, Day 8, Day 15 TAK-228 4mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 TAK-117 200mg Days 2-4, Days 9-11, Days 16-18, Days 23-25

Drug: paclitaxel; Drug: TAK-228; Drug: TAK-117

Interventions

paclitaxel DRUG

Paclitaxel will be diluted prior to infusion in 0.9% Sodium Chloride for Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer's Injection to a final concentration of 0.3 to 1.2mg/mL. At ambient temperature (approximately 25°C) and room lighting conditions the solution is physically and chemically stable for up to 27 hours. The diluted product will be prepared and stored in glass, polypropylene, or polyolefin containers; DEHP-containing (polyvinyl chloride (PCV)) containers should not be used. Paclitaxel will be administered using a vented Paclitaxel set with in-line 0.22-micron filter and run over 1 hour.

Also known as: Taxol

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5

TAK-228 DRUG

TAK-228 will be provided in 30-ct, 60-cc high density polyethylene (HDPE) bottles with polypropylene, child-resistant caps and induction seal. TAK-228 will be administered on an empty stomach. It is recommended that each dose of TAK-228 + TAK-117 be given PO with 8 ounces (240 mL) of water. Patients should be instructed to refrain from eating and drinking (except for water and prescribed medications) for 2 hours before and 1 hour after each dose.

Also known as: INK128, MLN0128

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5

TAK-117 DRUG

TAK-117 will be provided in 30-ct, 60-cc high density polyethylene (HDPE) bottles with polypropylene, child-resistant caps and induction seal. TAK-117 will be administered on an empty stomach. It is recommended that each dose of TAK-228 + TAK-117 be given PO with 8 ounces (240 mL) of water. Patients should be instructed to refrain from eating and drinking (except for water and prescribed medications) for 2 hours before and 1 hour after each dose.

Also known as: MLN1117, INK1117

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5

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 patients 18 years or older
• Patients must have a diagnosis of an advanced solid tumor malignancy and must be refractory to or intolerant of existing therapies known to provide a clinical benefit
• Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status of 0-2
• Female patients who:
• Are postmenopausal for at least 1 year before the screening visit, OR
• Are surgically sterile, OR
• If they are of childbearing potential must have a negative pregnancy test and agree to practice one effective method of pregnancy prevention contraception and one additional effective (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer as mandated by local labeling \[e.g., USPI, SmPC, etc.,\]) 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 \[e.g., calendar, ovulation, sympto- thermal and post ovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
• Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:
• Agree to practice highly effective barrier contraception during the entire study treatment period and through 120 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 \[e.g., calendar, ovulation, sympto- thermal and post ovulation methods for the female partner\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
• Agree not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug
• Screening clinical laboratory values as specified below:
• Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥1.5 x 109/L; platelet count ≥100 x 109/L; hemoglobin ≥9 g/dL without transfusion within 1-week preceding study drug administration
• Hepatic: total bilirubin ≤1.5 x upper limit of normal (ULN), transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase- AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) ≤2.5 x ULN (≤5 x ULN if liver metastases are present)

You may not qualify if:

• Active central nervous system (CNS) metastasis
• Other clinically significant co-morbidities, in the opinion of the investigators, 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
• 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 non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• Breast feeding or pregnant
• Treatment with any investigational products within 30 days before the first dose of study drug
• Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, TORC1/2 inhibitors (prior treatment with everolimus is allowed)
• Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of TAK-228. In addition, patients with small bowel or jejunal stomata are also excluded.

Sponsors & Collaborators

• Avera McKennan Hospital & University Health Center: lead

Study Sites (1)

Avera Cancer Institute

Sioux Falls, South Dakota, 57105, United States

Location

Related Publications (1)

• Starks DC, Rojas-Espaillat L, Meissner T, Williams CB. Phase I dose escalation study of dual PI3K/mTOR inhibition by Sapanisertib and Serabelisib in combination with paclitaxel in patients with advanced solid tumors. Gynecol Oncol. 2022 Sep;166(3):403-409. doi: 10.1016/j.ygyno.2022.07.005. Epub 2022 Jul 15.

  PMID: 35843739 DERIVED

MeSH Terms

Interventions

Paclitaxel; sapanisertib; serabelisib

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Results Point of Contact

• Title: Dr. Casey Williams
• Organization: Avera Cancer Institute

Casey.Williams@avera.org

605-322-3588

Study Officials

• Casey Williams, PharmD

  Avera Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Model Details: The demographic and clinical characteristics of the study patients will be summarized using descriptive statistics * Primary objective: The maximum tolerable dose will be assessed, which is the dose level at which \< one-third of patients will experience a dose-limiting toxicity * Secondary objectives: 1. Adverse events will be defined according to the Common Terminology Criteria for Adverse Events v4 and will be summarized with descriptive statistics 2. Response rate will be determined according to the Response Evaluation Criteria in Solid Tumors 1.1 response criteria. Number and type of responses will be summarized with descriptive statistics * Exploratory objectives 1. Response rate and relationship with genomic alterations will be examined by using a two-sided Fisher Exact test due to the small sample sizes 2. Therapy-Related Symptom Checklist and Health-Related Quality of Life Linear Analogue Self-Assessment scores will be summarized with descriptive statistics

Study Record Dates

• First Submitted: May 8, 2017
• First Posted: May 16, 2017
• Study Start: July 6, 2017
• Primary Completion: November 20, 2020
• Study Completion: November 20, 2022
• Last Updated: July 26, 2024
• Results First Posted: July 26, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)