GI-101/GI-101A as a Single Agent or in Combination With Pembrolizumab or Lenvatinib in Advanced Solid Tumors

A Phase 1/2, Open-label, Dose-escalation, Dose-optimization and Expansion Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Therapeutic Activity of GI-101/GI-101A as a Single Agent and in Combination With Pembrolizumab or Lenvatinib in Patients With Advanced or Metastatic Solid Tumors (Keynote B59)

This is a Phase 1/2, open-label, dose-escalation, dose-optimization and expansion study to evaluate safety, tolerability, pharmacokinetics, and therapeutic activity of GI-101/GI-101A as a single agent and in combination with pembrolizumab or lenvatinib in patients with advanced or metastatic solid tumors (Keynote B59)

This study will comprise six parts.

* Part A: Dose-escalation and expansion cohorts of GI-101 monotherapy
* Part B: Dose-escalation and expansion cohorts of GI-101 plus pembrolizumab
* Part C: Dose-optimization and expansion cohorts of GI-101 plus lenvatinib
* Part E: Dose-escalation cohorts of GI-101A monotherapy
* Part F: Dose-escalation cohorts of GI-101A plus pembrolizumab
* Part G: Dose-optimization and indication-specific cohorts of GI-101A plus pembrolizumab

* Part G1: Dose optimization cohorts in CPI-refractory urothelial cancer
* Part G2: Indication-specific cohorts in CPI-refractory ccRCC, squamous cell NSCLC and SoC-experienced MSS/pMMR CRC

GI-101/GI-101A is a novel bi-specific Fc fusion protein containing the CD80 ectodomain as an N-terminal moiety and an interleukin (IL)-2 variant as a C-terminal moiety configurated via a human immunoglobulin G4 (IgG4) Fc.

GI-101A is an abbreviation of advanced GI-101 with an improved formulation for manufacture consistency.

Drug Information available for: Pembrolizumab (https://www.keytrudahcp.com), Lenvatinib (http://www.lenvima.com)

Key Inclusion Criteria:

* Males and females aged ≥ 18 years (or ≥ 19 years according to local regulatory guidelines) at the time of screening.
* Has adequate organ and marrow function as defined in protocol.
* Measurable disease as per RECIST v1.1.
* ECOG performance status 0-1.
* Adverse events related to any prior chemotherapy, radiotherapy, immunotherapy, other prior systemic anti-cancer therapy, or surgery must have resolved to Grade ≤1, except alopecia and Grade 2 peripheral neuropathy.
* HIV infected patients must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease as defined in protocol.

Key Exclusion Criteria:

* Has known active CNS metastases and/or carcinomatous meningitis.
* An active second malignancy
* Has active or a known history of Hepatitis B or known active Hepatitis C virus infection.
* Has active tuberculosis or has a known history of active tuberculosis
* Active or uncontrolled infections, or severe infection within 4 weeks before study treatment administration.
* History of chronic liver disease or evidence of hepatic cirrhosis, except patients with liver metastasis.
* Has an active autoimmune disease that has required systemic treatment in past 2 years.
* Previous immunotherapies related to mode of action of GI-101.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive medications within 2 weeks prior to Cycle 1 Day 1.
* Administration of prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to treatment.
* Radiotherapy within the last 2 weeks before start of study treatment administration, with exception of limited field palliative radiotherapy
* Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1.
* Known hypersensitivity to any of the components of the drug products and/or excipients of GI-101/GI-101A, pembrolizumab or lenvatinib.

Other protocol defined inclusion exclusion criteria may apply. Cancer type and part-specific inclusion criteria are described in the study protocol.

Recommended phase 2 dose of GI-101 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).

Pembrolizumab will be administered at a dose of 200 mg as IV infusion Q3W.

Lenvatinib will be administered at an approved dose orally.

Recommended phase 2 dose of GI-101A will be administered via IV infusion Q3W up to 2 years (approximately 35 years).

Dose escalation: GI-101, multiple ascending doses

Dose expansion:

Dose escalation: GI-101, multiple ascending doses

Dose expansion:

Dose optimization:

Dose expansion:

Dose escalation: GI-101A, multiple ascending doses

Dose escalation: GI-101A, multiple ascending doses Dose optimization Indication-specific cohorts