NCT01296555 - A Dose Escalation Study Evaluating the Safety and Tolerability of GDC-0032 in Participants With Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma (NHL) and in Combination With Endocrine Therapy in Locally Advanced or Metastatic Hormone Receptor-Positive Breast Cancer | Crick

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Phase I (Cohorts A through D, G, H, T, T2 and X): Histologically documented, locally advanced or metastatic solid malignancy or NHL that has progressed or failed to respond to at least one prior regimen and are not candidates for regimens known to provide clinical benefit * Phase I (Cohorts E and F): Post-menopausal females with locally advanced or metastatic hormone receptor-positive breast cancer that has progressed or failed to respond to at least one prior endocrine therapy in the adjuvant or metastatic setting * Phase I (Cohorts J through S): Post-menopausal females with HER2-negative, hormone-receptor positive breast cancer that has progressed or failed to response to at least one prior endocrine therapy in the adjuvant or metastatic setting * Phase II: Post-menopausal female participants with locally advanced or metastatic HER2-negative, hormone receptor-positive breast cancer * Phase I (Cohorts A through S) and Phase II: Evaluable or measurable disease per RECIST version 1.1 * Phase I (Cohorts T, and T2): Greater than or equal to (\>/=) 1 bi-dimensionally measurable lesion on computed tomography (CT) scan * Phase I (Cohort T): Participants with non-Hodgkin's lymphoma, regardless of PIK3CA mutation status * Phase 1 (Cohort T2): Participants with diffuse large B-cell lymphoma (DLBCL), regardless of PIK3CA mutation status * Phase I (Cohort X): Participants with PIK3CA-mutant tumors and measurable disease per RECIST v1.1 * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at Screening * Life expectancy of \>/= 12 weeks * Adequate hematologic and organ function within 28 days prior to initiation of study treatment * Documented willingness to use an effective means of contraception for both men and women while participating in the study Exclusion Criteria: * Known and untreated, or active central nervous system (CNS) metastases (progressing or requiring treatment) * Active congestive heart failure or ventricular arrhythmia requiring medication * Participants requiring any daily supplemental oxygen * Active inflammatory disease requiring immunosuppressants, including small or large intestinal inflammation such as Crohn's disease or ulcerative colitis * Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis * Treatment with chemotherapy less than or equal to (\</=) 3 weeks before study treatment * Oral endocrine therapy \</= 2 weeks before study treatment * Treatment with investigational drug \</= 3 weeks or 5 half-lives before study treatment * Treatment with biologic therapy \</= 3 weeks before study treatment * Treatment with kinase inhibitors \</= 2 weeks before study treatment * Radiation therapy (other than radiation to bony metastases) as cancer therapy \</= 4 weeks before study treatment * Palliative radiation therapy to bony metastases \</= 2 weeks before study treatment * Major surgery \</= 4 weeks before study treatment * Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or renders the participant at high risk from treatment complications (examples include but are not limited to clinically significant non-healing wound, active bleeding, or ongoing fistula or active tuberculosis infection)

Outcomes

Primary Outcomes

Phase I Stage 1: Percentage of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0)

A DLT is defined as any one of the following toxicities occurring within the DLT Assessment Window (Days 1-35 of Cycle 1 in Stage 1) assessed by the investigator: Grade ≥ 3 non-hematologic, non-hepatic organ system, non-metabolic (hyperglycemia and hyperlipidemia) toxicity, excluding alopecia of any grade, Grade 3 diarrhea, Grade 3 nausea or vomiting; Grade ≥ 4 thrombocytopenia; Grade ≥ 4 neutropenia lasting \> 5 days or accompanied by fever; Fasting Grade ≥ 4 hyperglycemia or ≥ 3 hyperglycemia for ≥ 1 week; Grade ≥ 4 fasting hypercholesterolemia or triglyceridemia for ≥ 2 weeks; Grade ≥ 3 serum bilirubin or hepatic transaminase (ALT or AST); For participants abnormal at baseline: hepatic transaminase ≥ 7.5 × the upper limit of normal (ULN) or total bilirubin ≥ 5 × the ULN or 10 × the ULN or alkaline phosphatase ≥ 10 times the ULN.

Time frame: Baseline up to 35 days of Cycle 1

Phase I Stage 2 Cohorts E and F: Percentage of Participants With DLTs as Assessed by NCI CTCAE v4.0

A DLT is defined as any one of the following toxicities occurring within the DLT Assessment Window (Days 1-28 of Cycle 1 in Stage 1) assessed by the investigator: Grade ≥ 3 non-hematologic, non-hepatic organ system, non-metabolic (hyperglycemia and hyperlipidemia) toxicity, excluding alopecia of any grade, Grade 3 diarrhea, Grade 3 nausea or vomiting; Grade ≥ 4 thrombocytopenia; Grade ≥ 4 neutropenia lasting \> 5 days or accompanied by fever; Fasting Grade ≥ 4 hyperglycemia or ≥ 3 hyperglycemia for ≥ 1 week; Grade ≥ 4 fasting hypercholesterolemia or triglyceridemia for ≥ 2 weeks; Grade ≥ 3 serum bilirubin or hepatic transaminase (ALT or AST); For participants abnormal at baseline: hepatic transaminase ≥ 7.5 × ULN or total bilirubin ≥ 5 × the ULN or 10 × the ULN or alkaline phosphatase ≥ 10 times the ULN.

Time frame: Baseline up to 28 days of Cycle 1

Phase I: AUC From Zero to Tau (AUCtau) of GDC-0032

The concentrations are in micromole (µM), and the molecular weight of GDC-0032 is 460.53 g/mol.

Time frame: Cycle 1, Day 1: Pre-dose (0-2 hours [hr]), 0.5, 1, 2, 3, 4, 8, 24, 48 and 72 hr; Day 15: Pre-dose (0-2 hr), 0.5, 1, 2, 3, 4, 8 and 24 hr

Phase I: Maximum Observed Plasma Concentration (Cmax) of GDC-0032

The concentrations are in micromole (µM), and the molecular weight of GDC-0032 is 460.53 g/mol.

Time frame: Cycle 1, Day 1: Pre-dose (0-2 hours [hr]), 0.5, 1, 2, 3, 4, 8, 24, 48 and 72 hr; Day 15: Pre-dose (0-2 hr), 0.5, 1, 2, 3, 4, 8 and 24 hr

Phase I: Time to Reach Cmax (Tmax) of GDC-0032

Time frame: Cycle 1, Day 1: Pre-dose (0-2 hours [hr]), 0.5, 1, 2, 3, 4, 8, 24, 48 and 72 hr

Phase I: Terminal Half-life (t1/2) of GDC-0032

Time frame: Cycle 1, Day 1: Pre-dose (0-2 hours [hr]), 0.5, 1, 2, 3, 4, 8, 24, 48 and 72 hr

Across All Cohorts (Except Cohorts T and T2): Percentage of Participants With Best Overall Response (BOR) as Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

BOR was defined as having best objective response as complete response (CR) or partial response (PR), as assessed by RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.

Time frame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)

Across All Cohorts (Except Cohorts T and T2): Duration of Objective Response (DOR) as Assessed Using RECIST v1.1

DOR was defined as the time from the first occurrence of a documented objective response (OR) to progressive disease (PD) or death from any cause (whichever occurred first) as determined by the investigator according to RECIST v1.1. OR=CR+PR. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm. Number of participants analyzed signifies the number of responders.

Time frame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)

Across All Cohorts (Except Cohorts T and T2): Progression-Free Survival (PFS) as Assessed Using RECIST v1.1

PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause (whichever occurred first), as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).

Time frame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)

Percentage of Participants With BOR in Cohort T and T2

BOR in Cohort T was assessed using the 2007 Revised International Working Group (IWG) Response Criteria in Malignant Lymphoma while in Cohort T2, BOR was assessed using the Modified Version of 2014 Lugano Response Criteria in Malignant Lymphoma.

Time frame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)

DOR in Cohort T and T2

DOR in Cohort T was assessed using the 2007 Revised IWG Response Criteria in Malignant Lymphoma while in Cohort T2, it was assessed using the Modified Version of 2014 Lugano Response Criteria in Malignant Lymphoma. Number of participants analyzed signifies the number of responders.

Time frame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)

PFS in Cohort T and T2

PFS in Cohort T was assessed using the 2007 Revised IWG Response Criteria in Malignant Lymphoma while in Cohort T2, it was assessed using the Modified Version of 2014 Lugano Response Criteria in Malignant Lymphoma.

Time frame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)

Secondary Outcomes

Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) by NCI CTCAE v4.0 Grade

An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. An SAE is any AE that is fatal, life-threatening, requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity, a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s) or considered a significant medical event by the investigator.

Time frame: From first dose up to 30 days after the last dose of study drug or study discontinuation/termination (Up to a maximum of 16 months)

Phase I Stage 2: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade

An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an IMP or other protocol-imposed intervention, regardless of attribution. An SAE is any AE that is fatal, life-threatening, requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity, a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s) or considered a significant medical event by the investigator.

Time frame: From first dose up to 30 days after the last dose of study drug or study discontinuation/termination (Up to a maximum of 67 months)

Phase II: Percentage of Participants With AEs and SAEs by NCI CTCAE v4.0 Grade

Time frame: From first dose up to 30 days after the last dose of study drug or study discontinuation/termination (Up to a maximum of 54 months)

Percentage of Participants With Clinically Relevant Shifts From Baseline in Laboratory Parameters

A Dose Escalation Study Evaluating the Safety and Tolerability of GDC-0032 in Participants With Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma (NHL) and in Combination With Endocrine Therapy in Locally Advanced or Metastatic Hormone Receptor-Positive Breast Cancer

Overview

Conditions

Interventions

Eligibility

Locations (31)

Outcomes

Primary Outcomes

Secondary Outcomes