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

Genentech

Status and phase: Terminated; Phase 1

Conditions: Non-Hodgkin's Lymphoma; Solid Cancers

Treatments: Drug: Midazolam; Drug: GDC-0032; Drug: Letrozole; Drug: Fulvestrant

Study type: Interventional

Funder types: Industry

Identifiers

NCT01296555

PMT4979g

2012-002042-21 (EudraCT Number)

GO00886 (Other Identifier)

Details and patient eligibility

About

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.

Enrollment: 674 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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674 participants in 6 patient groups

Phase I, Stage 1: GDC-0032 as Single Agent

Experimental group

Description:

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.

Treatment:

Drug: GDC-0032

Phase I, Stage 2: GDC-0032 + Fulvestrant

Experimental group

Description:

Participants (Cohorts F, J, K, L, and M) will receive GDC-0032 in combination with fulvestrant until disease progression.

Treatment:

Drug: Fulvestrant

Drug: GDC-0032

Phase I, Stage 2: GDC-0032 + Letrozole

Experimental group

Description:

Participants (Cohorts E, N, P, Q, R, and S) will receive GDC-0032 in combination with letrozole until disease progression.

Treatment:

Drug: Letrozole

Drug: GDC-0032

Phase I, Stage 2: GDC-0032 as Single Agent

Experimental group

Description:

Participants (Cohorts A, B, C, D, G, H, T, T2, and X) will receive GDC-0032 until disease progression.

Treatment:

Drug: GDC-0032

Phase I, Stage 2: GDC-0032 + Midazolam

Experimental group

Description:

Participants (Cohort C) will receive GDC-0032 in combination with midazolam.

Treatment:

Drug: GDC-0032

Drug: Midazolam

Phase II: GDC-0032 + Fulvestrant

Experimental group

Description:

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.

Treatment:

Drug: Fulvestrant

Drug: GDC-0032