Sponsor Decision

This is an open-label, single-arm, Phase 1b/2 study designed to evaluate the safety, tolerability, and preliminary efficacy of milademetan in combination with atezolizumab in patients with advanced solid tumors with confirmed homozygous CDKN2A loss and WT TP53 who have progressed on or are refractory to prior PD-1/PD-L1 inhibitor therapy and who, in the opinion of the Investigator, are unlikely to tolerate or derive clinically meaningful benefit from other therapy.

This study will determine the recommended dose of milademetan when given in combination with atezolizumab (the combination RP2D) using a dose de-escalation safety assessment cohort (Phase 1b).

Following identification of the combination RP2D, the safety profile and preliminary anti-tumor activity of the combination RP2D will be evaluated in a larger population in a dose expansion cohort (Phase 2).

Up to 30 patients will be enrolled, 3 to 18 patients in the safety assessment cohort and 12 to 27 patients in the dose expansion cohort.

Key Inclusion Criteria:

• Has a histologically confirmed, advanced solid tumor that has progressed on prior therapy with an anti-PD-1/L1 inhibitor administered as either monotherapy or in combination with other therapies
• Has documented homozygous CDKN2A loss and Wild-Type TP53
• Confirmation of available tumor tissue collected within 5 years of enrollment
• Measurable tumor lesions per RECIST 1.1
• Estimate life expectancy of at least 6 months
• ECOG PS of 0 or 1
• Resolution of clinically relevant toxic effect of prior anti-cancer therapies Note: AEs from prior therapy must resolve to Grade ≤ 1 per the NCI CTCAE version 5.0, except for peripheral neuropathy, which must resolve to Grade ≤ 2, and alopecia
• Adequate bone marrow, renal and hepatic function

Key Exclusion Criteria:

• Has received prior treatment with any MDM2 inhibitor; prior treatment with atezolizumab is allowed except if the patient discontinued due to toxicity

• Has a history of any Grade 3 or 4 immune-related toxicities to a prior checkpoint inhibitor treatment or history of treatment discontinuation with prior checkpoint inhibitor use due to toxicity

  • Endocrinopathies which are stable with appropriate hormonal supplementation consistent with other eligibility parameters
  • Dermatologic events which have resolved to Grade ≤ 1 on stable medication, as appropriate, and consistent with other eligibility parameters

• Treatment with systemic immunosuppressive medication, including but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor agents, within 2 weeks prior to the first dose of study treatment or anticipation of need for systemic immunosuppressive medication during the course of the study

• Has an uncontrolled infection within the 7 days prior to Screening

• Has undergone treatment with therapeutic oral or IV antibiotics within 2 weeks prior to first dose of study treatment

• Has known active central nervous metastases and/or carcinomatous meningitis. Note: Patients who require steroids for brain metastases must be on a stable or tapering dose of corticosteroids for at least 2 weeks before the first dose of study treatment. If applicable, patients must complete stereotactic radiosurgery 7 days before, and spinal or whole brain radiotherapy 21 days before, their first dose of study treatment

• Has as other primary malignancies that have required systemic antineoplastic treatment within 2 years prior to Screening, except for localized cancers that have apparently been cured (eg, nonmelanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast) and will not interfere with the study outcomes

• Has uncontrolled or significant cardiovascular disease