Docetaxel With or Without TAK-117 (MLN1117) in Participants With Locally Advanced or Metastatic Non-small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine the recommended phase 2 dose (RP2D) of TAK-117 when administered in combination with docetaxel in participants with non-small cell lung cancer (NSCLC) and to evaluate efficacy, safety, and tolerability of TAK-117 administered alone and in combination with docetaxel at the RP2D in participants with locally advanced or metastatic non-small cell lung cancer.

Detailed Description
-----------------
The drug being evaluated in this study is called TAK-117. TAK-117 is tested in combination with docetaxel versus docetaxel alone for the treatment of non-small cell lung cancer (NSCLC). This study consisted of 2 phases: Phase 1b - dose escalation phase Phase 2 - expansion phase. The study enrolled 14 patients with NSCLC who have been treated with multiple prior lines of therapies will be enrolled for Phase 1b. The participants will receive docetaxel (36 mg/m^2) intravenous (IV) and TAK-117 tablets, orally administered, once daily in 21-day dosing cycles. The TAK-117 dose will be escalated until recommended Phase 2 dose (RP2D) is determined. Each part of the adaptive Phase 2 portion of the study is designed as a stand-alone, randomized study evaluating PFS as the primary efficacy measure in a total of 60 participants between the 2 treatment arms: TAK-117 plus docetaxel versus docetaxel alone. An event-driven analysis of PFS will be performed after each part of Phase 2. On the basis of the PFS analysis of the preceding part of the study, the study may be stopped for efficacy or futility, or proceed to the next part. However, Phase 2 of the study was cancelled. Study drug will be administered in 21-day dosing cycles. During each phase of the study, participants will be treated with a maximum of 9 cycles of either docetaxel alone or docetaxel plus TAK-117. Subsequently, participants treated with docetaxel plus TAK-117 may continue to receive TAK-117 monotherapy until progression of disease, occurrence of unacceptable toxicities or death. The maximum duration of treatment for participants will be 12 months unless it is determined that a participant would derive benefit from continued treatment beyond 12 months. Participants will continue to be followed after discontinuation of study drug to collect PFS and OS data. Participants may withdraw from therapy at any time. This multicenter trial will be conducted in North America. The overall time to participate in this study is up to 24 months.

Official Title
-----------------
A Phase 1b/Adaptive Phase 2 Study of Docetaxel With or Without MLN1117 in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer

Conditions
-----------------
Non-small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: Docetaxel
* Drug: TAK-117


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Has a histologically and/or cytologically confirmed diagnosis of NSCLC (squamous or nonsquamous). - For Phase 2 of the study, has a diagnosis of mixed squamous and nonsquamous (or adenosquamous) NSLC. Has locally advanced or metastatic disease (Stage IIIb or Stage IV) with radiographically or clinically evaluable lesions. Has experienced failure of at least 1 prior chemotherapy regimen: For Phase 2 of the study: Participants must have received 1 prior platinum-based chemotherapy regimen (excluding a docetaxel-containing regimen) for advanced or metastatic (Stage IIIb or Stage IV) disease followed by documented progressive disease (PD). A drug provided as maintenance therapy following cytotoxic chemotherapy will be considered to be part of that regimen. Participants who received prior therapy with paclitaxel as a part of the platinum-based doublet front-line regimen without PD on therapy. Participants who, after the front-line, platinum-based, non-docetaxel containing chemotherapy, have been treated with 1 line of nivolumab or other immune-checkpoint inhibitors but progressed on or after the therapy. For Phase 1b of the study: Participants who have experienced failure of multiple lines of prior chemotherapy are eligible. For Phase 2, has archived or fresh tumor biopsy samples (obtained during screening) sufficient for genotyping. Has adequate organ function, before the first dose of study drug. Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Female participants who are postmenopausal for at least 1 year before the screening visit or are surgically sterile, or are of childbearing potential, agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 30 days (or longer, as mandated by local labeling) after the last dose of study drug, or agree to practice true abstinence. Female participants must agree to not donate eggs (ova) during the course of this study and for 30 days after receiving their last dose of TAK-117 and, for docetaxel, for as long as is mandated by local labeling. Male participants agree to practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of TAK-117 and, for docetaxel, for as long as is mandated by local labeling, or agree to practice true abstinence. Male participants must agree to not donate sperm during the course of the study and for 120 days after receiving their last dose of TAK-117 and, for docetaxel, for as long as is mandated by local labeling. Has suitable venous access for the study-required blood sampling. Has recovered (ie, <= Grade 1 toxicity or eligibility per this protocol is met) from the reversible effects of prior anticancer therapy. In the opinion of the investigator, the participant or legal guardian is capable of understanding and complying with protocol requirements for the duration of the study. Exclusion Criteria: Previous treatment with a PI3K or AKT inhibitor. Prior cancer therapy or other investigational therapy within 2 weeks before the first administration of study drug or failed to recover from the reversible effects of prior anticancer therapies. 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 progressive disease. Has poorly controlled diabetes mellitus defined as HbA1c > 6.5%. Has taken strong inhibitors or strong inducers of CYP3A4 within 14 days before the first dose of study drug. Has taken histamine-H2 receptor antagonists and/or neutralizing antacids within 24 hours before the first administration of study drug. Has taken proton pump inhibitors within 7 days before the first administration of study drug. Has a condition that requires the concomitant use of any of the protocol-excluded medications, supplements, or food products during the course of the study . Has any clinically significant co-morbidities. Has acute myocardial infarction within 6 months before starting study drug, current or history of New York Heart Association Class III or IV heart failure; evidence of current uncontrolled cardiovascular conditions including cardiac arrhythmias, angina, pulmonary hypertension, or electrocardiogram (ECG) evidence of acute ischemia or active conduction system abnormalities; Fridericia's corrected QT interval > 475 milliseconds (msec) (males) or > 450 msec (females) on a 12-lead ECG during the Screening period; or abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and intervals that in the opinion of the investigator are considered to be clinically significant. Has known, previously diagnosed human immunodeficiency virus infection or active chronic hepatitis B or C. Has brain metastasis, unless has completed definitive therapy, is not on steroids, has a stable neurologic status for at least 2 weeks after completion of the definitive therapy and steroids, and does not have neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Has active secondary malignancy that requires treatment. Has any serious medical or psychiatric illness, including drug or alcohol abuse. Male participants who intend to donate sperm during the course of this study or 120 days after receiving their last dose of TAK-117 and, for docetaxel, for as long as is mandated by local labeling. 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 administration of the first dose of study drug. Is unwilling or unable to abide by the requirements of the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAK-117 200 mg + Docetaxel (36 mg/m^2)<br>TAK-117 200 mg, tablets, orally on Days 2, 3, 4, 9, 10, 11, 16, 17, and 18 of the 21-day cycle and docetaxel 36 mg/m^2, intravenous (IV) infusion, on Days 1 and 8 of the 21-day cycle up ro Cycle 9 (approximately 189 days). | Drug: Docetaxel<br>* Docetaxel intravenous infusion<br>Drug: TAK-117<br>* TAK-117 Tablets<br>* Other names: MLN1117;|
| Experimental: TAK-117 300 mg + Docetaxel 36 mg/m^2<br>TAK-117 200 mg, tablets, orally on Days 2, 3, 4, 9, 10, 11, 16, 17, and 18 of the 21-day cycle and docetaxel 36 mg/m^2, IV infusion, on Days 1 and 8 of the 21-day cycle up to 6 cycles (approximately 126 days). | Drug: Docetaxel<br>* Docetaxel intravenous infusion<br>Drug: TAK-117<br>* TAK-117 Tablets<br>* Other names: MLN1117;|
| Experimental: Phase 2 - TAK-117 + Docetaxel 36 mg/m^2<br>TAK-117 tablets, at the dose determined in the dose escalation phase, on Days 2, 3, 4, 9, 10, 11, 16, 17, and 18 of a 21-day cycle plus Docetaxel 36 mg/m^2 IV infusion on Days 1 and 8 of a 21-day cycle. | Drug: Docetaxel<br>* Docetaxel intravenous infusion<br>Drug: TAK-117<br>* TAK-117 Tablets<br>* Other names: MLN1117;|
| Experimental: Phase 2 - Docetaxel 75 mg/m^2<br>Docetaxel 75 mg/m^2, IV infusion once every 3 weeks (per approved prescribing information) with dosing on Day 1 of each 21-day cycle. | Drug: Docetaxel<br>* Docetaxel intravenous infusion<br>Drug: TAK-117<br>* TAK-117 Tablets<br>* Other names: MLN1117;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicity (DLT) in Phase 1b | DLT was evaluated according to National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 and was defined as any of the following events: 1. Grade 4 neutropenia or thrombocytopenia lasting ≥7 consecutive days; 2. Grade 4 neutropenia with fever and/or infection; 3. Platelet count <10,000/mm^3; 4. ≥Grade 3 thrombocytopenia with bleeding; 5. Any other ≥Grade 4 hematologic toxicity; 6. Any other ≥Grade 3 nonhematologic toxicity, with following exceptions: ≥Grade 3 arthralgia/myalgia, ≥Grade 3 nausea/emesis, ≥Grade 3 diarrhoea, Grade 3 fatigue, Grade 3 Rash, Grade 3 nonhematological toxicity that could be controlled to ≤Grade 1 with appropriate treatment; 7. Inability to administer at least 75% of planned doses; 8. Clinically significant occurrence per investigator that is a safety risk. | Cycle 1 (Up to Day 21) | 
| Maximum Tolerated Dose (MTD) of TAK-117 in Combination With Docetaxel 36 mg/m^2 in Phase 1b | The MTD is defined as the dose of TAK-117 in combination with docetaxel 36 mg/m^2 at which 1 of 6 evaluable participants experience DLT. DLT was evaluated according to NCI CTCAE version 4.03 and was defined as any of the following events: 1. Grade 4 neutropenia or thrombocytopenia lasting ≥7 consecutive days; 2. Grade 4 neutropenia with fever and/or infection; 3. Platelet count <10,000/mm^3; 4. ≥Grade 3 thrombocytopenia with bleeding; 5. Any other ≥Grade 4 hematologic toxicity; 6. Any other ≥Grade 3 nonhematologic toxicity, with following exceptions: ≥Grade 3 arthralgia/myalgia, ≥Grade 3 nausea/emesis, ≥Grade 3 diarrhoea, Grade 3 fatigue, Grade 3 Rash, Grade 3 nonhematological toxicity that could be controlled to ≤Grade 1 with appropriate treatment; 7. Inability to administer at least 75% of planned doses; 8. Clinically significant occurrence per investigator that is a safety risk. | Cycle 1 (Up to Day 21) | 
| Recommended Phase 2 Dose of TAK-117 in Phase 1b | The recommended phase 2 dose was determined in Phase 1b based on participant dose-limiting toxicities and the maximum tolerated dose. | Cycle 1 (Up to Day 21) | 
| Progression-Free Survival (PFS) in Phase 2 | PFS is defined as the time from the date randomization to the date of first documented progressive disease (PD) or death as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease. | Approximately 12 months in Phase 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Significant Change in Vital Signs Reported as Adverse Events in Phase 1b | Clinically significant change from baseline in vital sign measures will be assessed. Vital sign measurements included measurements of diastolic and systolic blood pressure, heart rate, and temperature. | First dose of study drug through 30 days after the last dose of study drug (Up to Day 223) | 
| Number of Participants With Significant Change in Physical Examination Reported as Adverse Events in Phase 1b | Physical examination consists of examinations of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) physical examinations other than body systems described in (1) to (10). | First dose of study drug through 30 days after the last dose of study drug (Up to Day 223) | 
| Number of Participants With Electrocardiogram (ECG) Findings Reported as Adverse Events in Phase 1b | A standard 12-lead ECG was performed. | First dose of study drug through 30 days after the last dose of study drug (Up to Day 223) | 
| Number of Participants With Clinically Significant Change in Clinical Laboratory Tests Reported as Adverse Events in Phase 1b | The number of participants with any markedly abnormal standard safety laboratory values (Chemistry, Hematology and Urinalysis) collected throughout study. | First dose of study drug through 30 days after the last dose of study drug (Up to Day 223) | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) in Phase 1b | An Adverse Event (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. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. | From first dose of study drug to 30 days after last dose of study drug (Up to Day 223) | 
| Number of Participants With Significant Change in Vital Signs Reported as Adverse Events in Phase 2 | Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study. | Approximately 12 months in Phase 2 | 
| Number of Participants With Significant Change in Physical Examination Reported as Adverse Events in Phase 2 | Physical examination consists of examinations of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) physical examinations other than body systems described in (1) to (10). | Approximately 12 months in Phase 2 | 
| Number of Participants With Electrocardiogram (ECG) Findings Reported as Adverse Events in Phase 2 | Clinically significant changes from baseline in ECGs will be tabulated by time point including any unscheduled measurements. | Approximately 12 months in Phase 2 | 
| Number of Participants With Clinically Significant Change in Clinical Laboratory Tests Reported as Adverse Events in Phase 2 | The number of participants with any markedly abnormal standard safety laboratory values (Chemistry, Hematology and Urinalysis) collected throughout study. | Approximately 12 months in Phase 2 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) in Phase 2 | An Adverse Event (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. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. | Approximately 12 months in Phase 2 | 
| Response Rate in Phase 2 | Response rate is defined as the percentage of participants with Complete Response (CR) + Partial Response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1. According to RECIST: CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter of target lesions. | Approximately 12 months in Phase 2 | 
| Disease Control Rate in Phase 2 | Disease control rate is defined as percentage of participants with CR + PR + stable disease (SD). According to RECIST: CR is defined as disappearance of all target lesions, PR is defined as 30% decrease in the sum of the longest diameter of target lesions and SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter (LD) since the treatment started. | Approximately 12 months in Phase 2 | 
| Duration of Response in Phase 2 | The duration of response is defined as the time from the date of first documentation of a response to the date of first documentation of progression of disease. As per RECIST 1.1, PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease. | Approximately 12 months in Phase 2 | 
| Time to Progression in Phase 2 | Time to progression is defined as the time from the date of randomization to the date of first documentation of progression of disease. As per RECIST 1.1, PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease. | Approximately 12 months in Phase 2 | 
| Overall Survival (OS) in Phase 2 | Overall survival is defined as the time from the date of randomization to the date of death. | Approximately 12 months in Phase 2 | 
| TAK-117 Plasma Concentration in Phase 1b |  | Cycle 1 Day 1 pre-dose and 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose | 
| Cmax: Maximum Observed Plasma Concentration for TAK-117 |  | Cycle 1 Day 1 pre-dose and 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-117 |  | Cycle 1 Day 1 pre-dose and up to 24 hours post-dose | 
| AUCtau: Area Under the Concentration Time Curve From Time 0 to the Next Dose in Phase 1b for TAK-117 |  | Cycle 1 Day 1 pre-dose and up to 24 hours post-dose | 
| AUC(Last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration in Phase 1b for TAK-117 |  | Cycle 1 Day 1 pre-dose and up to 24 hours post-dose | 
| CL/F: Oral Clearance for TAK-117 |  | Cycle 1 Day 1 pre-dose and up to 24 hours post-dose | 
| T1/2: Terminal Phase Elimination Half-life (T1/2) for TAK-117 |  | Cycle 1 Day 1 pre-dose and up to 24 hours post-dose | 
| TAK-117 Plasma Concentrations When Administered 1 Day After Docetaxel in Phase 2 |  | 1 day post docetaxel dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Drug therapy