Solid CancersPhase 1NCT01296555
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
A Phase 1 study testing Fulvestrant, GDC-0032 and Letrozole in people with Solid Cancers and Non-Hodgkin's Lymphoma, run by Genentech, Inc. at 31 sites in 4 countries.
Trial summary
This is an open-label, multicenter, Phase I/II study to assess the safety, tolerability, and pharmacokinetics of GDC-0032. The Phase I portion will be divided into two stages. During Stage 1, GDC-0032 will be administered every day orally and at escalating doses in participants with locally advanced or metastatic… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Solid Cancers, Non-Hodgkin's Lymphoma
- What is being tested?
- Fulvestrant, GDC-0032 and Letrozole
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 674 participants
- Where
- 31 sitesin 4 countries
- Study dates
- 16 Mar 2011to 25 Jun 2021
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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)
Trial locations and contacts
31 sites in 4 countries.
31 sites in 4 countries
United States27 sites
Texas Cancer Center
Abilene, Texas, 79606-5208
New York Oncology Hematology, P.C.
Albany, New York, 12206
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02114
Dana Farber Cancer Inst.
Boston, Massachusetts, 02115
Univ of Chicago
Chicago, Illinois, 60637
Mary Crowley Cancer Rsch Ctr
Dallas, Texas, 75230
Baylor Sammons Cancer Center
Dallas, Texas, 75246
Barbara Ann Karmanos Cancer Institute
Detroit, Maine, 48201-2013
Florida Cancer Specialists - Fort Myers (New Hampshire Ct)
Fort Myers, Florida, 33901-8101
West Cancer Center
Germantown, Tennessee, 38138
MD Anderson Cancer Center
Houston, Texas, 77030
Sarah Cannon Res Inst; TN Onc
Nashville, Tennessee, 37203
Vanderbilt Breast Center; Vanderbilt Health Pharmacy
Nashville, Tennessee, 37204
Vanderbilt
Nashville, Tennessee, 37232
Yale University
New Haven, Connecticut, 06510
Memorial Sloan-Kettering Cancer Center
New York, New York, 10065
Sarah Cannon Res Inst; OK
Oklahoma City, Oklahoma, 73104
University of California Irvine Medical Center
Orange, California, 92868
UC Davis; Comprehensive Cancer Center
Sacramento, California, 95817
Sutter Health
San Francisco, California, 94109
Sarah Cannon Res Inst; FL
Sarasota, Florida, 34232
TGen Clinical Research Srvs
Scottsdale, Arizona, 85258
Washington University; Division of Oncology
St Louis, Missouri, 63110
University of Arizona Cancer Center
Tucson, Arizona, 85719
USO - Tyler Cancer Ctr
Tyler, Texas, 75702
Northwest Cancer Specialists - Vancouver
Vancouver, Washington, 98684
Yakima Valley Memorial Hospital/North Star Lodge
Yakima, Washington, 98902
Spain2 sites
Hospital Univ Vall d'Hebron; Servicio de Oncologia
Sant Andreu de la Barca, Barcelona, 08740
Hospital Clinico Universitario de Valencia
Valencia, 46010
Canada1 site
University Health Network; Princess Margaret Hospital; Medical Oncology Dept
Toronto, Ontario, M5G 2M9
About this study
Official title: An Open-Label, Phase I/II, Dose-Escalation Study Evaluating the Safety and Tolerability of GDC-0032 in Patients With Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma and in Combination With Endocrine Therapy in Patients With Locally Advanced or Metastatic Hormone Receptor-Positive Breast Cancer
This is an open-label, multicenter, Phase I/II study to assess the safety, tolerability, and pharmacokinetics of GDC-0032. The Phase I portion will be divided into two stages. During Stage 1, GDC-0032 will be administered every day orally and at escalating doses in participants with locally advanced or metastatic solid tumors. During Stage 2, GDC-0032 will be administered alone or as combination therapy within indication-specific cohorts. In Phase II of the study, the efficacy and safety of the combination GDC-0032 and fulvestrant will be evaluated in post-menopausal female participants with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative, hormone receptor-positive breast cancer.
- Conditions
- Solid Cancers, Non-Hodgkin's Lymphoma
- Being tested
- Fulvestrant, GDC-0032, Letrozole, Midazolam
- Medical subject headings
- Lymphoma, Non-Hodgkin
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FulvestrantDrug
Also called Faslodex®
Participants will receive fulvestrant 500 milligrams (mg) via intramuscular injection (as per package insert or Summary of Product Characteristics [SmPC]) on Days 1 and 15 of Cycle 1, then on Day 1 of each subsequent cycle, until disease progression (Cycle length: 28 days).
GDC-0032Drug
Participants will receive GDC-0032 at escalating (Phase I, Stage 1) or fixed (Phase II and Phase I, Stage 2) doses until disease progression. Cycle 1 may be 35 days in length to allow for a 7-day washout following the initial dose; thereafter, GDC-0032 will be administered orally once daily in 28-day cycles.
LetrozoleDrug
Also called Femara®
Participants will receive letrozole 2.5 mg orally (as per Package Insert or SmPC) once daily in 28-day cycles until disease progression.
MidazolamDrug
Participants will receive midazolam 5 mg (as per Package Insert or SmPC) in hydrochloride syrup on Days 1 and 16 of Cycle 1.
| Study group | Role | What they receive |
|---|---|---|
| Phase I, Stage 1: GDC-0032 as Single Agent | Experimental | Participants with locally advanced or metastatic solid tumors will receive increasing doses of GDC-0032 administered orally daily in 28-day cycles. Dose escalation decisions will be based upon the observed incidence of DLTs. Receives: Drug: GDC-0032 |
| Phase I, Stage 2: GDC-0032 + Fulvestrant | Experimental | Participants (Cohorts F, J, K, L, and M) will receive GDC-0032 in combination with fulvestrant until disease progression. Receives: Drug: Fulvestrant; Drug: GDC-0032 |
| Phase I, Stage 2: GDC-0032 + Letrozole | Experimental | Participants (Cohorts E, N, P, Q, R, and S) will receive GDC-0032 in combination with letrozole until disease progression. Receives: Drug: GDC-0032; Drug: Letrozole |
| Phase I, Stage 2: GDC-0032 as Single Agent | Experimental | Participants (Cohorts A, B, C, D, G, H, T, T2, and X) will receive GDC-0032 until disease progression. Receives: Drug: GDC-0032 |
| Phase I, Stage 2: GDC-0032 + Midazolam | Experimental | Participants (Cohort C) will receive GDC-0032 in combination with midazolam. Receives: Drug: GDC-0032; Drug: Midazolam |
| Phase II: GDC-0032 + Fulvestrant | Experimental | Post-menopausal females with locally advanced or metastatic HER2-negative, hormone receptor-positive breast cancer will receive GDC-0032 in combination with fulvestrant until disease progression. Receives: Drug: Fulvestrant; Drug: GDC-0032 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)
Secondary outcomes (10)
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.
Measured: 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.
Measured: 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
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.
Measured: 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
Laboratory parameters such as fasting glucose, absolute neutrophil count, hemoglobin, platelet count, lymphocytes, serum creatinine, aspartate aminotransferase (AST), alanine transaminase (ALT), leukocytes, fasting triglycerides and fasting cholesterol were assessed. A clinically relevant shift from baseline was defined as a shift from Grade 0, 1, or 2 at baseline to Grade 3 or 4 post baseline.
Measured: Baseline to a maximum of 67 months
Cmax of GDC-0032 Under Fed Conditions
For dosing under fed conditions, participant fasted overnight for >/= 10 hours before the standard high-fat meal provided at the study site. Participants started the standard high fat meal 30 minutes prior to administration of GDC-0032.
Measured: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
Cmax of GDC-0032 Under Fasted Conditions
Participants fasted overnight for at least 10 hours before dosing and 4 hours postdose.
Measured: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
AUC of GDC-0032 Under Fed Conditions
For dosing under fed conditions, participant fasted overnight for >/= 10 hours before the standard high-fat meal provided at the study site. Participants started the standard high fat meal 30 minutes prior to administration of GDC-0032.
Measured: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
AUC of GDC-0032 Under Fasted Conditions
Participants fasted overnight for at least 10 hours before dosing and 4 hours postdose.
Measured: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
Geometric Mean Ratio of Cmax for Midazolam Plus GDC-0032 Relative to Cmax for Midazolam Alone
The geometric mean ratio (90% CI) for midazolam+ GDC-0032 relative to midazolam alone was reported. Geometric Mean Ratio of Cmax was determined by comparing Midazolam Geometric Mean on Day 16 to Midazolam Geometric Mean on Day 1 (GeoMeanD16/GeoMeanD1).
Measured: Cycle 1, Day 1: Pre-dose (0-2 hr), 0.5, 1, 1.5, 2, 4, 8, 24 hr; Day 16: Pre-dose (0-2 hr), 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hr
Geometric Mean Ratio of AUC for Midazolam Plus GDC-0032 Relative to AUC for Midazolam Alone
The geometric mean ratios (90% CIs) for midazolam + GDC-0032 relative to midazolam alone were reported. Geometric Mean Ratio is determined by comparing GeoMean of AUC D16 with GeoMean of AUC D1 (GeoMeanD16/GeoMeanD1).
Measured: Cycle 1, Day 1: Pre-dose (0-2 hr), 0.5, 1, 1.5, 2, 4, 8, 24 hr; Day 16: Pre-dose (0-2 hr), 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hr
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Feb 2011 (estimated)
- Study start16 Mar 2011
- Primary completion25 Jun 2021
- Study completion25 Jun 2021
Why it stopped: The Sponsor discontinued the manufacturing and development of taselisib due to modest clinical benefit and limited tolerability.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Solid CancersStudies of the same condition, open and under way.
- More trials run by Genentech, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 674 participants (actual)
Sponsor and investigators
- Lead sponsor
- Genentech, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Clinical Trials, Study director, Genentech, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01296555
- Sponsor's protocol ID
- PMT4979g
- Other IDs
- GO00886, 2012-002042-21
- Status last verified
- Feb 2024
- First submitted
- 14 Feb 2011
- Last updated
- 31 Jul 2024
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Moein A, Jin JY, Wright MR, Wong H. Quantitative characterization of the effects of fulvestrant alone or in combination with taselisib (PI3Kinase inhibitor) on longitudinal tumor growth in patients with estrogen receptor-positive, HER2-negative, PIK3CA-mutant, advanced or metastatic breast cancer. Cancer Chemother Pharmacol. 2024 Sep;94(3):421-436. doi: 10.1007/s00280-024-04690-4. Epub 2024 Jun 27.
PubMed 38937298
Study at a glance
From the registry record, last updated by the sponsor on 31 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-Label, Phase I/II, Dose-Escalation Study Evaluating the Safety and Tolerability of GDC-0032 in Patients With Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma and in Combination With Endocrine Therapy in Patients With Locally Advanced or Metastatic Hormone Receptor-Positive Breast Cancer
- ClinicalTrials.gov ID
- NCT01296555
- Acronym / sponsor ID
- PMT4979g
- Conditions
- Solid Cancers, Non-Hodgkin's Lymphoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The Sponsor discontinued the manufacturing and development of taselisib due to modest clinical benefit and limited tolerability.
- Enrolment
- 674 participants (actual)
- Lead sponsor
- Genentech, Inc.Industry (pharma, biotech, devices)
- Study start
- 16 Mar 2011 (actual)
- Primary completion
- 25 Jun 2021 (actual)
- Study completion
- 25 Jun 2021 (actual)
- First posted
- 15 Feb 2011 (estimated)
- Results
- Posted 31 Jul 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is an open-label, multicenter, Phase I/II study to assess the safety, tolerability, and pharmacokinetics of GDC-0032. The Phase I portion will be divided into two stages. During Stage 1, GDC-0032 will be administered every day orally and at escalating doses in participants with locally advanced or metastatic solid tumors. During Stage 2, GDC-0032 will be administered alone or as combination therapy within indication-specific cohorts. In Phase II of the study, the efficacy and safety of the combination GDC-0032 and fulvestrant will be evaluated in post-menopausal female participants with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative, hormone receptor-positive breast cancer.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Phase I, Stage 1: GDC-0032 as Single Agent | Experimental | Drug: GDC-0032Participants with locally advanced or metastatic solid tumors will receive increasing doses of GDC-0032 administered orally daily in 28-day cycles. Dose escalation decisions will be based upon the observed incidence of DLTs. |
| Phase I, Stage 2: GDC-0032 + Fulvestrant | Experimental | Drug: Fulvestrant, Drug: GDC-0032Participants (Cohorts F, J, K, L, and M) will receive GDC-0032 in combination with fulvestrant until disease progression. |
| Phase I, Stage 2: GDC-0032 + Letrozole | Experimental | Drug: GDC-0032, Drug: LetrozoleParticipants (Cohorts E, N, P, Q, R, and S) will receive GDC-0032 in combination with letrozole until disease progression. |
| Phase I, Stage 2: GDC-0032 as Single Agent | Experimental | Drug: GDC-0032Participants (Cohorts A, B, C, D, G, H, T, T2, and X) will receive GDC-0032 until disease progression. |
| Phase I, Stage 2: GDC-0032 + Midazolam | Experimental | Drug: GDC-0032, Drug: MidazolamParticipants (Cohort C) will receive GDC-0032 in combination with midazolam. |
| Phase II: GDC-0032 + Fulvestrant | Experimental | Drug: Fulvestrant, Drug: GDC-0032Post-menopausal females with locally advanced or metastatic HER2-negative, hormone receptor-positive breast cancer will receive GDC-0032 in combination with fulvestrant until disease progression. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FulvestrantAlso: Faslodex®Participants will receive fulvestrant 500 milligrams (mg) via intramuscular injection (as per package insert or Summary of Product Characteristics [SmPC]) on Days 1 and 15 of Cycle 1, then on Day 1 of each subsequent cycle, until disease progression (Cycle length: 28 days). | Drug | Phase I, Stage 2: GDC-0032 + Fulvestrant, Phase II: GDC-0032 + Fulvestrant |
| GDC-0032Participants will receive GDC-0032 at escalating (Phase I, Stage 1) or fixed (Phase II and Phase I, Stage 2) doses until disease progression. Cycle 1 may be 35 days in length to allow for a 7-day washout following the initial dose; thereafter, GDC-0032 will be administered orally once daily in 28-day cycles. | Drug | Phase I, Stage 1: GDC-0032 as Single Agent, Phase I, Stage 2: GDC-0032 + Fulvestrant, Phase I, Stage 2: GDC-0032 + Letrozole, Phase I, Stage 2: GDC-0032 + Midazolam, Phase I, Stage 2: GDC-0032 as Single Agent, Phase II: GDC-0032 + Fulvestrant |
| LetrozoleAlso: Femara®Participants will receive letrozole 2.5 mg orally (as per Package Insert or SmPC) once daily in 28-day cycles until disease progression. | Drug | Phase I, Stage 2: GDC-0032 + Letrozole |
| MidazolamParticipants will receive midazolam 5 mg (as per Package Insert or SmPC) in hydrochloride syrup on Days 1 and 16 of Cycle 1. | Drug | Phase I, Stage 2: GDC-0032 + Midazolam |
Primary outcome
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)
Time frame: Baseline up to 35 days of Cycle 1
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.
Phase I Stage 2 Cohorts E and F: Percentage of Participants With DLTs as Assessed by NCI CTCAE v4.0
Time frame: Baseline up to 28 days of Cycle 1
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.
Phase I: AUC From Zero to Tau (AUCtau) 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; Day 15: Pre-dose (0-2 hr), 0.5, 1, 2, 3, 4, 8 and 24 hr
The concentrations are in micromole (µM), and the molecular weight of GDC-0032 is 460.53 g/mol.
Phase I: Maximum Observed Plasma Concentration (Cmax) 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; Day 15: Pre-dose (0-2 hr), 0.5, 1, 2, 3, 4, 8 and 24 hr
The concentrations are in micromole (µM), and the molecular weight of GDC-0032 is 460.53 g/mol.
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)
Time frame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)
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.
Across All Cohorts (Except Cohorts T and T2): Duration of Objective Response (DOR) as Assessed Using RECIST v1.1
Time frame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)
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.
Across All Cohorts (Except Cohorts T and T2): Progression-Free Survival (PFS) as Assessed Using RECIST v1.1
Time frame: Baseline up to disease progression or death, whichever occurred first (up to a maximum of 67 months)
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).
Percentage of Participants With BOR in Cohort T and T2
Time frame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)
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.
DOR in Cohort T and T2
Time frame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)
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.
PFS in Cohort T and T2
Time frame: Baseline up to disease progression or death, whichever occurs first (up to a maximum of 46 months)
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.
10 secondary outcomes
Phase I Stage 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (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 16 months)
Phase I Stage 2: 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 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
Time frame: Baseline to a maximum of 67 months
Cmax of GDC-0032 Under Fed Conditions
Time frame: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
Cmax of GDC-0032 Under Fasted Conditions
Time frame: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
AUC of GDC-0032 Under Fed Conditions
Time frame: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
AUC of GDC-0032 Under Fasted Conditions
Time frame: Cycle 1, Day 1: Pre-dose (0-2 hr), 1, 2, 3, 4, 8, and 24 hr
Geometric Mean Ratio of Cmax for Midazolam Plus GDC-0032 Relative to Cmax for Midazolam Alone
Time frame: Cycle 1, Day 1: Pre-dose (0-2 hr), 0.5, 1, 1.5, 2, 4, 8, 24 hr; Day 16: Pre-dose (0-2 hr), 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hr
Geometric Mean Ratio of AUC for Midazolam Plus GDC-0032 Relative to AUC for Midazolam Alone
Time frame: Cycle 1, Day 1: Pre-dose (0-2 hr), 0.5, 1, 1.5, 2, 4, 8, 24 hr; Day 16: Pre-dose (0-2 hr), 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hr
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jul 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38937298Moein A, Jin JY, Wright MR, Wong H. Quantitative characterization of the effects of fulvestrant alone or in combination with taselisib (PI3Kinase inhibitor) on longitudinal tumor growth in patients with estrogen receptor-positive, HER2-negative, PIK3CA-mutant, advanced or metastatic breast cancer. Cancer Chemother Pharmacol. 2024 Sep;94(3):421-436. doi: 10.1007/s00280-024-04690-4. Epub 2024 Jun 27.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clinical Trials study director
Genentech, Inc.
31 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Fulvestrant, GDC-0032 and Letrozole in people with Solid Cancers and Non-Hodgkin's Lymphoma, run by Genentech, Inc. at 31 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 31 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 31 sites in United States, Spain, Canada, France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 31 Jul 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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) (time frame: Baseline up to 35 days of Cycle 1). The study lists 12 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01296555, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jul 2024.