A Safety and Pharmacokinetic Study of TAK-228 in Combination With TAK-117 in Adult Participants With Advanced Nonhematologic Malignancies

The purpose of this study was to evaluate the safety and to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), and dosing schedules of oral TAK-228+TAK-117. It also evaluated the single- and multiple-dose plasma pharmacokinetics (PK) of TAK-228+TAK-117 in participants with advanced nonhematologic malignancies.

The drug being tested in this study was TAK-228. TAK-228 was tested to evaluate the safety, pharmacokinetics and efficacy, of TAK-228 in combination with TAK-117 when administered to adult participants with advanced nonhematologic malignancies.

The study enrolled 101 patients. The study consisted of 2 phases: an escalation stage followed by an expansion stage. Participants in escalation stage were assigned to the following treatment arms:

* Dose escalation treatment arm A: TAK-228 2 or 4 mg capsule
* Dose escalation treatment arm B: TAK-228 3, 4, 6 or 8 mg capsule
* Dose escalation treatment arm C: TAK-228 3 mg capsule

Upon completion of the escalation stage, 1 combination treatment regimen was selected for further safety, tolerability, pharmacokinetics, and mutual drug-drug interaction characterization in the expansion stage. During treatment, participants in both stages received TAK-228 and TAK-117 capsules at prespecified doses in repeated 28-day cycles.

This multi-center trial conducted in the United States, United Kingdom and Spain. The overall time to participate in this study was approximately 68 weeks. Participants made multiple visits to the clinic, and a final visit after 30 days after last dose of study drug.

Eligibility Criteria:
Inclusion Criteria:

* Male or female participants 18 years or older
* Participants must have a diagnosis and documented disease progression of a solid tumor malignancy, excluding primary brain tumor, for which standard, curative, or life prolonging treatment does not exist or is no longer effective
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Female participants who are postmenopausal for at least 1 year prior to screening. For women of child-bearing potential agree to practice 2 effective methods of contraception or agree to practice true abstinence
* Male participants must agree to practice effective barrier contraception during the entire study treatment period and through 30 days after last dose of study drug or practice true abstinence
* Voluntary written consent
* Suitable venous access
* Participants must have a block of banked tumor tissue and/or fresh tumor tissue or at least 10 unstained slides available to be sent to the central laboratory
* Clinical laboratory values as specified in the protocol
* Participants must have radiographically or clinically evaluable tumor

Exclusion Criteria:

* Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug
* Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment
* Treatment with any investigational products within 30 days before the first dose of study drug
* Previous treatment with TAK-117 and/or TAK-228; previous treatment with dual mTORC1/2 or dual PI3K-mTOR inhibitors
* Failed to have recovered from the reversible effects of previous anticancer therapies
* Have received systemic corticosteroid (inhalers are allowed) within 7 days before the first administration of study drug
* Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of study drug
* Diagnosis of diabetes mellitus
* Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active CNS disease, active infection
* Known human immunodeficiency virus (HIV) infection
* Cardiovascular conditions as defined in the protocol
* A requirement for positive inotropic support (excluding digoxin) or serious uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation) within 1 year before screening
* Participants who are taking proton pump inhibitors within 7 days of the first dose or who require treatment with proton pump inhibitors during the trial or those who are taking histamine-2 (H2) receptor antagonists within 24 hours of the first dose
* Participants who received previous therapy with PI3K inhibitors or rapalogs will be allowed in the study if all other inclusion/exclusion criteria are met
* Diagnosis of primary brain tumor or symptomatic brain metastasis. Participants with brain metastases must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events (AEs)