This is a Phase I open-label, multi-center study of zamzetoclax (formerly GS-9716) tested either as monotherapy or in combination with other anti-cancer agents in patients with advanced solid malignancies. Primary objectives are to define the maximum tolerated dose (MTD) or maximum administered dose of zamzetoclax, and characterize the safety and tolerability of zamzetoclax as monotherapy and in combination with anti-cancer therapies.

Key Inclusion Criteria:

General Inclusion Criteria (all cohorts):

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Measurable disease per RECIST version 1.1
• Adequate hematology, renal and hepatic function
• Left ventricular ejection fraction (LVEF) ≥ 50%
• Patients with brain metastases may be enrolled only if treated, nonprogressive, asymptomatic and not taking high dose steroids for at least 4 weeks prior to Cycle 1 Day 1 (C1D1)
• Individuals of childbearing potential who engage in heterosexual intercourse must agree to use method(s) of contraception, per protocol.
• Tissue criteria: must provide sufficient, and adequate tumor tissue sample or agree to have a biopsy taken.

Part A Specific Inclusion Criteria: zamzetoclax as monotherapy

• Histologically or cytologically confirmed locally advanced or metastatic malignant solid tumor for which no standard therapy is available, standard therapy has failed, or for whom standard-of-care therapy is contraindicated.

Cohorts B1 and C1 Specific Inclusion Criteria:

• Histologically or cytologically confirmed unresectable metastatic or locally advanced disease following treatment for metastatic disease including an immune checkpoint inhibitor and a platinum-containing chemotherapy
• Patients with actionable genomic alterations must have also received treatment with at least 1 approved therapy appropriate to the genomic alteration unless unavailable or contraindicated

Cohorts B4 and C4 Specific Inclusion Criteria:

• Histologically or cytologically confirmed disease based on the most recent analyzed biopsy metastatic disease that is refractory to or relapsed after at least 2 prior standard-of-care chemotherapy regimens, one of which was a taxane (unless contraindicated).

Key Exclusion Criteria:

• Prior systemic anti-cancer therapy must meet wash-out criteria outlined in protocol
• Treatment with any high dose systemic corticosteroids or nonsystemic radiotherapy within 2 weeks of the first dose of zamzetoclax (low dose corticosteroids permitted).
• Women who are pregnant or lactating
• Patients with active ≥ Grade 2 nausea or vomiting, and/or signs of intestinal obstruction
• Known active or chronic hepatitis B or C infection or HIV infection/ HIV positive
• Known history of clinically significant cardiovascular disease or heart failure.
• Known history of clinically significant active chronic obstructive pulmonary disease or other moderate to severe chronic respiratory illness present within 6 months prior to C1D1
• Known history of other clinically significant pulmonary disease or evidence of active pneumonitis
• Uncontrolled pleural effusion, pericardial effusion, or ascites
• History of clinically significant bleeding, intestinal obstruction, or gastrointestinal (GI) perforation within 6 months prior to C1D1
• Infection requiring intravenous anti-infective use within 2 weeks prior to C1D1
• Active or history of autoimmune disease or immune deficiency
• History of uncured coexisting cancer, not including uncured basal cell carcinoma, cervical cancer in situ, or superficial bladder cancer.

Cohort A Specific Exclusion Criteria: zamzetoclax as monotherapy:

• Known heart failure or elevated cardiac biomarkers

Cohorts B1 and C1 Specific Exclusion Criteria:

• Known hypersensitivity to excipients in study treatments.

Cohorts B4 and C4 Specific Exclusion Criteria:

• Prior treatment with sacituzumab govitecan-hziy or a topoisomerase 1 inhibitor or agents targeting Trop-2.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.