This study will evaluate PF-05212384 (gedatolisib) PI3K/mTOR inhibitor)) in combination with either docetaxel, cisplatin or dacomitinib in select advanced solid tumors. The study will assess the safety, pharmacokinetics and pharmacodynamics of these combinations in patients with advanced cancer in order to determine the maximum tolerated dose in each combination. The cisplatin combination expansion portion will evaluate the anti tumor activity of PF 05212384 plus cisplatin in patients with TNBC in 2 separate Arms (Arm 1 and Arm 2).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
110
PF-05212384 weekly intravenous infusions starting at 90 mg/wk as a 3 week cycle
Docetaxel intravenous infusions once every 3 weeks starting at 75 mg/m\^2
Cisplatin intravenous infusions once every 3 weeks starting at 75 mg/m\^2
Dacomitinib to be taken orally as a continuous once daily regimen at a starting dose of 30 mg
University of Alabama at Birmingham
Birmingham, Alabama, United States
University of Alabama at Birmingham
Birmingham, Alabama, United States
Ronald Reagan UCLA Medical Center
Los Angeles, California, United States
UCLA Hematology Oncology
Los Angeles, California, United States
Westwood Bowyer Clinic
Los Angeles, California, United States
Number of Participants With Dose Limiting Toxicities (DLTs) - Arms A, B and C
DLT was defined as any of the following adverse events (AEs) attributable to the combination: (1) hematologic: grade 4 neutropenia lasting \>7 days; febrile neutropenia; grade \>=3 neutropenia with infection; grade 3 thrombocytopenia with bleeding; grade 4 thrombocytopenia; (2) non-hematologic: grade \>=2 pneumonitis; grade\>=3 toxicities, except pneumonitis, and excluding those that had not been maximally treated; persistent, intolerable toxicities which resulted in the failure to deliver at least 3 of the 4 doses of PF-05212384 for Arms A and B or at least 3 of the 4 doses of PF-05212384 and 75% of dacomitinib for Arm C during the first cycle; the persistent, intolerable toxicities which result in delay of the start of the second cycle by more than 2 weeks relative to the scheduled start; in an asymptomatic participant, the grade 3 QTc prolongation persists after correction of any reversible causes.
Time frame: Up to 21 days
Percentage of Participants With Objective Response - Arm B Expansion
Percentage of participants with objective response based on the assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. Per RECIST v1.1: CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm) and no new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease and no new lesions.
Time frame: Cycle 1 Day 1 up to 18 months
Number of Participants With Treatment-Emergent Adverse Events (All Causality) - Arms A, B, C and B Expansion
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participants administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. Treatment Emergent AEs were those occurred for the first time after the start of study treatment and within 28 days after final dose of study treatment and was not seen prior to the start of treatment, or those were seen prior to the start of study treatment but increased in Common Terminology Criteria for Adverse Events (CTCAE) grade after the start of study treatment and within 28 days after final dose of study treatment. AEs were graded by the investigator according to the CTCAE version 4.03 : Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE.
Time frame: From the first dose of study drugs up to 28 days after the last dose of study drugs. Maximum duration between first and last dose: 505 days for Arm A, 414 days for Arm B, 842 days for Arm C, 728 days for Arm B Expansion.
Number of Participants With Treatment-Emergent Adverse Events (Treatment Related) - Arms A, B, C and B Expansion
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participants administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. Treatment Emergent AEs were those occurred for the first time after the start of study treatment and within 28 days after final dose of study treatment and was not seen prior to the start of treatment, or those were seen prior to the start of study treatment but increased in Common Terminology Criteria for Adverse Events (CTCAE) grade after the start of study treatment and within 28 days after final dose of study treatment. AEs were graded by the investigator according to the CTCAE version 4.03 : Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE.
Time frame: From the first dose of study drugs up to 28 days after the last dose of study drugs. Maximum duration between first and last dose: 505 days for Arm A, 414 days for Arm B, 842 days for Arm C, 728 days for Arm B Expansion.
Number of Participants With Laboratory Abnormalities by Severity (All Cycles) - Hematology
Laboratory abnormalities were graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (Grade 0: no change from normal or reference range; Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated) and those with at least 1 participant are presented here. Following parameters were analyzed for laboratory examination: anemia,hemoglobin increased, platelets, white blood cells, absolute neutrophils,lymphocyte count increased, lymphopenia.
Time frame: From the first dose of study drugs up to 28 days after the last dose of study drugs. Maximum duration between first and last dose: 505 days for Arm A, 414 days for Arm B, 842 days for Arm C, 728 days for Arm B Expansion.
Number of Participants With Laboratory Abnormalities by Severity (All Cycles) - Coagulation
Laboratory abnormalities were graded per NCI CTCAE version 4.03 (Grade 0: no change from normal or reference range; Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated) and those with at least 1 participant are presented here. Following parameters were analyzed for laboratory examination: partial thromboplastin time and prothrombin time international normalized ratio(INR).
Time frame: From the first dose of study drugs up to 28 days after the last dose of study drugs. Maximum duration between first and last dose: 505 days for Arm A, 414 days for Arm B, 842 days for Arm C, 728 days for Arm B Expansion.
Number of Participants With Laboratory Abnormalities by Severity (All Cycles) - Chemistry
Laboratory abnormalities were graded per NCI CTCAE version 4.03 (Grade 0: no change from normal or reference range; Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated) and those with at least 1 participant are presented here. Following parameters were analyzed for laboratory examination: alanine aminotransferase (ALT), alkaline phosphatase, aspartate aminotransferase (AST), total bilirubin, creatinine, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, and hypophosphatemia.
Time frame: From the first dose of study drugs up to 28 days after the last dose of study drugs. Maximum duration between first and last dose: 505 days for Arm A, 414 days for Arm B, 842 days for Arm C, 728 days for Arm B Expansion.
Number of Participants With Laboratory Abnormalities by Severity (All Cycles) - Urinalysis
Laboratory abnormalities were graded per NCI CTCAE version 4.03 (Grade 0: no change from normal or reference range; Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated) and those with at least 1 participant are presented here. Following parameter was analyzed for laboratory examination: urine protein.
Time frame: From the first dose of study drugs up to 28 days after the last dose of study drugs. Maximum duration between first and last dose: 505 days for Arm A, 414 days for Arm B, 842 days for Arm C, 728 days for Arm B Expansion.
Number of Participants With Vital Signs Data Meeting Pre-defined Criteria
Blood pressure (BP), including systolic BP (SBP) and diastolic BP (DBP), and pulse rate were recorded in sitting position.
Time frame: From baseline up to follow up (at least 28 days and no more than 35 days after discontinuation of treatment). Maximum duration between first and last dose: 842 days.
Maximum Observed Plasma Concentration (Cmax) Following Single IV Infusion Dose of PF-05212384 Alone - Plasma PF-05212384 (Arms A, B and C)
Cmax is defined as maximum observed plasma concentration.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose 7 days prior to Cycle 1 Day 1 for Arms A and B; pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose 14 days prior to Cycle 1 Day 1 for Arm C.
Maximum Observed Plasma Concentration (Cmax) Following Single IV Infusion Dose of PF-05212384 in Combination With Cisplatin - Plasma PF-05212384 (Arm B Expansion)
Cmax is defined as maximum observed plasma concentration.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 (predose Day 8) hours post-dose on Cycle 1 Day 1.
Maximum Observed Plasma Concentration (Cmax) Following Multiple IV Infusion Doses of PF-05212384 in Combination With Docetaxel- Plasma PF-05212384 (Arm A)
Cmax is defined as maximum observed plasma concentration.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose on Cycle 2 Day 1.
Maximum Observed Plasma Concentration (Cmax) Following Multiple IV Infusion Doses of PF-05212384 in Combination With Cisplatin - Plasma PF-05212384 (Arm B)
Cmax is defined as maximum observed plasma concentration.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose on Cycle 2 Day 1.
Maximum Observed Plasma Concentration (Cmax) Following Multiple IV Infusion Doses of PF-05212384 in Combination With Dacomitinib - Plasma PF-05212384 (Arm C)
Cmax is defined as maximum observed plasma concentration.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose on Cycle 2 Day 1.
Maximum Observed Plasma Concentration (Cmax) Following Multiple IV Infusion Doses of PF-05212384 in Combination With Cisplatin - Plasma PF-05212384 (Arm B Expansion)
Cmax is defined as maximum observed plasma concentration.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 (predose Day 8) hours post-dose on Cycle 2 Day 1.
Maximum Observed Plasma Concentration (Cmax) Following Single IV Infusion Dose of Docetaxel Alone- Plasma Docetaxel (Arm A)
Cmax is defined as maximum observed plasma concentration.
Time frame: Pre-dose, 1, 1.5, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 1.
Maximum Observed Plasma Concentration (Cmax) Following Administration of Docetaxel IV Infusion in Combination With PF-05212384 - Plasma Docetaxel (Arm A)
Cmax is defined as maximum observed plasma concentration.
Time frame: Pre-dose, 1, 1.5, 2, 4, 6, and 24 hours post-dose on Cycle 2 Day 1.
Maximum Observed Plasma Concentration (Cmax) Following Single IV Infusion Dose of Cisplatin Alone - Plasma Platinum (Arm B)
Cmax is defined as maximum observed plasma concentration.
Time frame: Pre-dose, 2, 2.5, 3, 4, 6, and 24 hours post-dose on Cycle 1 Day 1.
Maximum Observed Plasma Concentration (Cmax) Following Administration of Cisplatin IV Infusion in Combination With PF-05212384 - Plasma Platinum (Arm B)
Cmax is defined as maximum observed plasma concentration.
Time frame: Pre-dose, 2, 2.5, 3, 4, 6, and 24 hours post-dose on Cycle 2 Day 1.
Maximum Observed Plasma Concentration (Cmax) Following Multiple Oral Doses of Dacomitinib Alone - Plasma Dacomitinib (Arm C)
Cmax is defined as maximum observed plasma concentration.
Time frame: Pre-dose, 1, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 1.
Maximum Observed Plasma Concentration (Cmax) Following Multiple Oral Doses of Dacomitinib in Combination With PF-05212384 - Plasma Dacomitinib (Arm C)
Cmax is defined as maximum observed plasma concentration.
Time frame: Pre-dose, 1, 2, 4, 6, and 24 hours post-dose on Cycle 2 Day 1.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) Following Single IV Infusion Dose of PF-05212384 Alone - Plasma PF-05212384 (Arms A, B and C)
AUClast is defined as area under the curve from time zero to last quantifiable concentration.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose 7 days prior to Cycle 1 Day 1 for Arms A and B; pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose 14 days prior to Cycle 1 Day 1 for Arm C.
Area Under the Concentration-time Profile From Time 0 to Time Tau (AUCtau) Following Multiple IV Infusion Doses of PF-05212384 in Combination With Docetaxel- Plasma PF-05212384 (Arm A)
AUCtau is defined as area under the concentration-time profile from time 0 to time tau.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose on Cycle 2 Day 1.
Area Under the Concentration-time Profile From Time 0 to Time Tau (AUCtau) Following Multiple IV Infusion Doses of PF-05212384 in Combination With Cisplatin - Plasma PF-05212384 (Arm B)
AUCtau is defined as area under the concentration-time profile from time 0 to time tau.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose 7 days prior to Cycle 2 Day 1.
Area Under the Concentration-time Profile From Time 0 to Time Tau (AUCtau) Following Multiple IV Infusion Doses of PF-05212384 in Combination With Dacomitinib - Plasma PF-05212384 (Arm C)
AUCtau is defined as area under the concentration-time profile from time 0 to time tau.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose on Cycle 2 Day 1.
Area Under the Concentration-time Profile From Time 0 to Time Tau (AUCtau) Following Single IV Infusion Dose of PF-05212384 in Combination With Cisplatin - Plasma PF-05212384 (Arm B Expansion)
AUCtau is defined as area under the concentration-time profile from time 0 to time tau.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 (predose Day 8) hours post-dose on Cycle 1 Day 1.
Area Under the Concentration-time Profile From Time 0 to Time Tau (AUCtau) Following Multiple IV Infusion Doses of PF-05212384 in Combination With Cisplatin - Plasma PF-05212384 (Arm B Expansion)
AUCtau is defined as area under the concentration-time profile from time 0 to time tau.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 (predose Day 8) hours post-dose on Cycle 2 Day 1.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) Following Single IV Infusion Dose of Docetaxel Alone- Plasma Docetaxel (Arm A)
AUClast is defined as area under the curve from time zero to last quantifiable concentration.
Time frame: Pre-dose, 1, 1.5, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 1.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) Following Administration of Docetaxel in Combination With PF-05212384 - Plasma Docetaxel (Arm A)
AUClast is defined as area under the curve from time zero to last quantifiable concentration.
Time frame: Pre-dose, 1, 1.5, 2, 4, 6, and 24 hours post-dose on Cycle 2 Day 1.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) Following Single IV Infusion Dose of Cisplatin Alone - Plasma Platinum (Arm B)
AUClast is defined as area under the curve from time zero to last quantifiable concentration.
Time frame: Pre-dose, 2, 2.5, 3, 4, 6, and 24 hours post-dose on Cycle 1 Day 1.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) Following Administration of Cisplatin IV Infusion in Combination With PF-05212384 - Plasma Platinum (Arm B)
AUClast is defined as area under the curve from time zero to last quantifiable concentration.
Time frame: Pre-dose, 2, 2.5, 3, 4, 6, and 24 hours post-dose on Cycle 2 Day 1.
Area Under the Concentration-time Profile From Time 0 to Time Tau (AUCtau) Following Multiple Oral Doses of Dacomitinib Alone - Plasma Dacomitinib (Arm C)
AUCtau is defined as area under the concentration-time profile from time 0 to time tau.
Time frame: Pre-dose, 1, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 1.
Area Under the Concentration-time Profile From Time 0 to Time Tau (AUCtau) Following Multiple Oral Doses of Dacomitinib in Combination With PF-05212384 - Plasma Dacomitinib (Arm C)
AUCtau is defined as area under the concentration-time profile from time 0 to time tau.
Time frame: Pre-dose, 1, 2, 4, 6, and 24 hours post-dose on Cycle 2 Day 1.
Time to Reach Maximum Observed Plasma Concentration (Tmax) Following Single IV Infusion Dose of PF-05212384 Alone - Plasma PF-05212384 (Arms A, B and C)
Tmax is defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose 7 days prior to Cycle 1 Day 1 for Arms A and B; pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose 14 days prior to Cycle 1 Day 1 for Arm C.
Time to Reach Maximum Observed Plasma Concentration (Tmax) Following Multiple IV Infusion Doses of PF-05212384 in Combination With Docetaxel- Plasma PF-05212384 (Arm A)
Tmax is defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose on Cycle 2 Day 1.
Time to Reach Maximum Observed Plasma Concentration (Tmax) Following Multiple IV Infusion Doses of PF-05212384 in Combination With Cisplatin - Plasma PF-05212384 (Arm B)
Tmax is defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose on Cycle 2 Day 1.
Time to Reach Maximum Observed Plasma Concentration (Tmax) Following Multiple IV Infusion Doses of PF-05212384 in Combination With Dacomitinib - Plasma PF-05212384 (Arm C)
Tmax is defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose on Cycle 2 Day 1.
Time to Reach Maximum Observed Plasma Concentration (Tmax) Following Single IV Infusion Dose of Docetaxel Alone- Plasma Docetaxel (Arm A)
Tmax is defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 1, 1.5, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 1.
Time to Reach Maximum Observed Plasma Concentration (Tmax) Following Administration of Docetaxel IV Infusion in Combination With PF-05212384 - Plasma Docetaxel (Arm A)
Tmax is defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 1, 1.5, 2, 4, 6, and 24 hours post-dose on Cycle 2 Day 1.
Time to Reach Maximum Observed Plasma Concentration (Tmax) Following Single IV Infusion Dose of Cisplatin Alone - Plasma Platinum (Arm B)
Tmax is defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 2, 2.5, 3, 4, 6, and 24 hours post-dose on Cycle 1 Day 1.
Time to Reach Maximum Observed Plasma Concentration (Tmax) Following Administration of Cisplatin IV Infusion in Combination With PF-05212384 - Plasma Platinum (Arm B)
Tmax is defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 2, 2.5, 3, 4, 6, and 24 hours post-dose on Cycle 2 Day 1.
Time to Reach Maximum Observed Plasma Concentration (Tmax) Following Multiple Oral Doses of Dacomitinib Alone - Plasma Dacomitinib (Arm C)
Tmax is defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 1, 2, 4, 6, and 24 hours post-dose on Cycle 1 Day 1.
Time to Reach Maximum Observed Plasma Concentration (Tmax) Following Multiple Oral Doses of Dacomitinib in Combination With PF-05212384 - Plasma Dacomitinib (Arm C)
Tmax is defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 1, 2, 4, 6, and 24 hours post-dose on Cycle 2 Day 1.
Time to Reach Maximum Observed Plasma Concentration (Tmax) Following Single IV Infusion Dose of PF-05212384 in Combination With Cisplatin - Plasma PF-05212384 (Arm B Expansion)
Tmax is defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 (predose Day 8) hours post-dose on Cycle 1 Day 1.
Time to Reach Maximum Observed Plasma Concentration (Tmax) Following Multiple IV Infusion Doses of PF-05212384 in Combination With Cisplatin - Plasma PF-05212384 (Arm B Expansion)
Tmax is defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 24, 72, 96 and 168 (predose Day 8) hours post-dose on Cycle 2 Day 1.
Mean Serum Biomarkers for Glucose - Baseline
A phosphatidylinositol 3 kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor should disrupt the cellular uptake and metabolism of glucose. This study employed metabolic biomarkers such as glucose as pharmacodynamics markers for dual PI3K/mTOR inhibition.
Time frame: Baseline
Mean Serum Biomarkers for Glucose - End of Treatment
A phosphatidylinositol 3 kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor should disrupt the cellular uptake and metabolism of glucose. This studies employed metabolic biomarkers such as glucose as pharmacodynamics markers for dual PI3K/mTOR inhibition.
Time frame: End of treatment. Maximum duration between first and last dose: 505 days for Arm A, 414 days for Arm B, 842 days for Arm C, 728 days for Arm B Expansion.
Mean Serum Biomarkers for Insulin - Baseline
A phosphatidylinositol 3 kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor should disrupt the cellular uptake and metabolism of glucose. This studies employed metabolic biomarkers such as insulin as pharmacodynamics markers for dual PI3K/mTOR inhibition.
Time frame: Baseline
Mean Serum Biomarkers for Insulin - End of Treatment
A phosphatidylinositol 3 kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor should disrupt the cellular uptake and metabolism of glucose. This studies employed metabolic biomarkers such as insulin as pharmacodynamics markers for dual PI3K/mTOR inhibition.
Time frame: End of treatment. Maximum duration between first and last dose: 505 days for Arm A, 414 days for Arm B, 842 days for Arm C, 728 days for Arm B Expansion.
Mean Serum Biomarkers for Hemoglobin A1c (HbA1c) - Baseline
A phosphatidylinositol 3 kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor should disrupt the cellular uptake and metabolism of glucose. This studies employed metabolic biomarkers such as hemoglobin A1c (HbA1c) as pharmacodynamics markers for dual PI3K/mTOR inhibition.
Time frame: Baseline
Mean Serum Biomarkers for Hemoglobin A1c (HbA1c) - End of Treatment
A phosphatidylinositol 3 kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor should disrupt the cellular uptake and metabolism of glucose. This studies employed metabolic biomarkers such as hemoglobin A1c (HbA1c) as pharmacodynamics markers for dual PI3K/mTOR inhibition.
Time frame: End of treatment. Maximum duration between first and last dose: 505 days for Arm A, 414 days for Arm B, 842 days for Arm C, 728 days for Arm B Expansion.
Percentage of Participants With BRAF and KRAS Mutations in Population of Breast Cancer - Arms A and C
Biopsies were obtained at screening and after drug administration. These samples were analyzed predominantly for phosphoprotein biomarkers indicative of pathway modulation, or for genetic markers correlated to drug sensitivity (eg, emerging KRAS mutation and BRAF mutation). BRAF mutation categories included BRAF mutation status and V600E. KRAS mutation categories included GLY12ALA, GLY12ARG, GLY12ASP, GLY12CYS, GLY12SER, GLY12VAL and GLY13ASP.
Time frame: Baseline
Percentage of Participants With BRAF and KRAS Mutations in Population of Non-Small Cell Lung Cancer - Arms A, B and C
Biopsies were obtained at screening and after drug administration. These samples were analyzed predominantly for phosphoprotein biomarkers indicative of pathway modulation, or for genetic markers correlated to drug sensitivity (eg, emerging KRAS mutation and BRAF mutation). BRAF mutation categories included BRAF mutation status and V600E. KRAS mutation categories included GLY12ALA, GLY12ARG, GLY12ASP, GLY12CYS, GLY12SER, GLY12VAL and GLY13ASP.
Time frame: Baseline
Percentage of Participants With BRAF and KRAS Mutations in Population of Prostate Cancer - Arm A
Biopsies were obtained at screening and after drug administration. These samples were analyzed predominantly for phosphoprotein biomarkers indicative of pathway modulation, or for genetic markers correlated to drug sensitivity (eg, emerging KRAS mutation and BRAF mutation). BRAF mutation categories included BRAF mutation status and V600E. KRAS mutation categories included GLY12ALA, GLY12ARG, GLY12ASP, GLY12CYS, GLY12SER, GLY12VAL and GLY13ASP.
Time frame: Baseline
Percentage of Participants With BRAF and KRAS Mutations in Population of Ovarian Cancer - Arm B
Biopsies were obtained at screening and after drug administration. These samples were analyzed predominantly for phosphoprotein biomarkers indicative of pathway modulation, or for genetic markers correlated to drug sensitivity (eg, emerging KRAS mutation and BRAF mutation). BRAF mutation category was BRAF mutation status. KRAS mutation categories included GLY12ALA, GLY12ARG, GLY12ASP, GLY12CYS, GLY12SER, GLY12VAL and GLY13ASP.
Time frame: Baseline
Percentage of Participants With BRAF and KRAS Mutations in Population of Transitional Cell Carcinoma - Arm B
Biopsies were obtained at screening and after drug administration. These samples were analyzed predominantly for phosphoprotein biomarkers indicative of pathway modulation, or for genetic markers correlated to drug sensitivity (eg, emerging KRAS mutation and BRAF mutation). BRAF mutation categories included BRAF mutation status and V600E. KRAS mutation categories included GLY12ALA, GLY12ARG, GLY12ASP, GLY12CYS, GLY12SER, GLY12VAL and GLY13ASP.
Time frame: Baseline
Percentage of Participants With BRAF and KRAS Mutations in Population of Triple Negative Breast Cancer - Arm B
Biopsies were obtained at screening and after drug administration. These samples were analyzed predominantly for phosphoprotein biomarkers indicative of pathway modulation, or for genetic markers correlated to drug sensitivity (eg, emerging KRAS mutation and BRAF mutation). BRAF mutation categories included BRAF mutation status and V600E. KRAS mutation categories included GLY12ALA, GLY12ARG, GLY12ASP, GLY12CYS, GLY12SER, GLY12VAL and GLY13ASP.
Time frame: Baseline
Percentage of Participants With BRAF and KRAS Mutations in Population of Head and Neck Cancer - Arm C
Biopsies were obtained at screening and after drug administration. These samples were analyzed predominantly for phosphoprotein biomarkers indicative of pathway modulation, or for genetic markers correlated to drug sensitivity (eg, emerging KRAS mutation and BRAF mutation). BRAF mutation categories included BRAF mutation status and V600E. KRAS mutation categories included GLY12ALA, GLY12ARG, GLY12ASP, GLY12CYS, GLY12SER, GLY12VAL and GLY13ASP.
Time frame: Baseline
Percentage of Participants With BRAF and KRAS Mutations in Population of Oesophageal Carcinoma - Arm C
Biopsies were obtained at screening and after drug administration. These samples were analyzed predominantly for phosphoprotein biomarkers indicative of pathway modulation, or for genetic markers correlated to drug sensitivity (eg, emerging KRAS mutation and BRAF mutation). BRAF mutation categories included BRAF mutation status and V600E. KRAS mutation categories included GLY12ALA, GLY12ARG, GLY12ASP, GLY12CYS, GLY12SER, GLY12VAL and GLY13ASP.
Time frame: Baseline
Number of Participants With Maximum Increase From Baseline in Corrected QT (QTc) Interval
Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR) and by Bazette's formula (QTcB = QT divided by square root of RR). Participants with maximum increase from baseline of 30 to less than (\<) 60 msec(borderline) and greater than or equal to (\>=) 60 msec (prolonged) were summarized.
Time frame: Baseline, Cycle 1 Day 1 (for Arm B Expansion), Cycle 1 Day 2 (for Arms A, B and C), Cycle 2 Day 1 (for Arms A, B and C), Day 1 for each cycle (Cycles 3-36, for Arms B Expansion and C) and end of treatment (up to 2 years, for Arms B Expansion and C).
Number of Participants With Maximum Corrected QT (QTc) Interval Meeting Pre-defined Criteria
QT interval corrected using Fridericia's formula (QTcF) and Bazette's formula (QTcB): QT interval (time corresponding to the beginning of depolarization to re-polarization of the ventricles) divided by cube root of RR interval. Maximum QTcF was categorized as less than (\<) 450 milliseconds (msec), 450 msec to 480 msec, 480 msec to 500 msec, and more than (\>) 500 msec.
Time frame: Baseline, Cycle 1 Day 1 (for Arm B Expansion), Cycle 1 Day 2 (for Arms A, B and C), Cycle 2 Day 1 (for Arms A, B and C), Day 1 for each cycle (Cycles 3-36, for Arms B Expansion and C) and end of treatment (up to 2 years, for Arms B Expansion and C).
Percentage of Participants With Objective Response - Arm A
Percentage of participants with objective response based on the assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Per RECIST v1.1: CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm) and no new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease and no new lesions.
Time frame: Baseline up to 18 months.
Percentage of Participants With Objective Response - Arm B
Percentage of participants with objective response based on the assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Per RECIST v1.1: CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm) and no new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease and no new lesions.
Time frame: Baseline up to 18 months.
Percentage of Participants With Objective Response - Arm C
Percentage of participants with objective response based on the assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Per RECIST v1.1: CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm) and no new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease and no new lesions.
Time frame: Baseline up to 18 months.
Clinical Benefit Response Rate - Arm B Expansion
Percent of participants with confirmed complete response (CR), partial response (PR) or stable disease (SD) for at least 24 weeks on study according to Response Evaluation Criteria in Solid Tumors (RECIST). Per RECIST v1.1: CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm) and no new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease and no new lesions. SD was defined as not qualifying for CR, PR, Progressive Disease (PD).
Time frame: Baseline up to 18 months.
Duration of Response - Arm B Expansion
Duration of response was calculated from first date of partial response (PR) or complete response (CR) to the date of progression or death due to any cause. In the event of no progression or death, the last tumor assessment date without progression was used in this calculation.
Time frame: Baseline up to 18 months.
Progression Free Survival - Arm B Expansion
Progression free survival (PFS) defined as the time from first dose of study treatment to date of first documentation of progression or death due to any cause, whichever occurs first. PFS was calculated as first event date minus the date of first dose of study medication plus 1 . Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease \[PD\]), or from adverse event (AE) data (where the outcome was "Death").
Time frame: Baseline up to 18 months.
Mean Observed Score Values for European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) - Arm B Expansion
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.
Time frame: Baseline, Day 1 and Day 8 of Cycles 1 and 2, Day 1 of Cycles 3 to 16.
Mean Change From Baseline for European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) - Arm B Expansion
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.
Time frame: Baseline, Day 1 and Day 8 of Cycles 1 and 2, Day 1 of Cycles 3 to 16.
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UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States
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Santa Monica, California, United States
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Aurora, Colorado, United States
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