First-in-Human Evaluation of GRN-300 in Subjects With Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers.

Ph 1/1B Evaluation of the Safety, Pharmacokinetics and Efficacy of GRN-300, a Salt-inducible Kinase Inhibitor, Alone and in Combination With Paclitaxel, in Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers.

The study consists of two parts based on the administration of single-agent GRN-300 or in combination with paclitaxel.

Part 1 (Phase IA) will test the tolerability of continuous twice a day dosing of oral GRN-300, a salt-inducible kinase inhibitor, with each cycle consisting of 28 days of treatment. The number of administered cycles will depend on the tolerability of each dose level and the severity and occurrence of dose limiting toxicities (DLTs) or adverse events.

Part 2 (Phase IB) will test the tolerability of continuous 28-day cycles of GRN-300 in combination with weekly paclitaxel given 3 of 4 weeks per month (x 3).

Overall duration of the study will be approximately 48 months, depending on the rate of enrollment and number of subjects enrolled.

Part 1: Phase 1A

Primary objectives:

Determination of the maximum tolerated dose (MTD), if applicable, and recommended Phase II dose (RP2D) of GRN-300 in the study population.

To investigate the safety and tolerability of repeated 28-day cycles of oral GRN-300 therapy in subjects with persistent or recurrent, locally non-resectable or metastatic ovarian, fallopian tube, and primary peritoneal cancer or other advanced solid tumors.

Secondary objectives:

To evaluate the pharmacokinetic (PK) profile of GRN-300 after oral administration of a single dose and at steady state.

To estimate the clinical activity of GRN-300 monotherapy by determining the following:

• Overall response rate (ORR) per investigator assessment using RECIST v1.1 defined as the percentage of subjects having a best overall response (BOR) of complete response (CR) or partial response (PR)
• Disease control rate (DCR) per investigator assessment using RECIST v1.1 defined as the percentage of subjects having a BOR of CR, PR, or stable disease (SD) ≥ 4 months (4 cycles, 28 days each).

Part 2: Phase 1B

Primary objectives:

Determination of the RP2D of GRN-300 in combination with weekly paclitaxel given 3 of 4 weeks per month (x 3) in the study population.

To investigate the safety and tolerability of repeated 28-day cycles of daily oral GRN-300 therapy in combination with weekly paclitaxel x 3 in subjects with persistent or recurrent, locally non-resectable or metastatic, ovarian, fallopian tube, and primary peritoneal cancer, where treatment with paclitaxel is appropriate.

Secondary objectives:

To evaluate the PK profile of GRN-300 and paclitaxel following administration of a single dose of each and at steady state.

To estimate the clinical activity of GRN-300 in combination with paclitaxel by determining the following:

• Overall response rate (ORR) per investigator assessment using RECIST v1.1 defined as the percentage of subjects having a best overall response (BOR) of complete response (CR) or partial response (PR)
• DCR per investigator assessment using RECIST v.1.1 defined as the percentage of subjects having a BOR of CR, PR, or SD ≥ 4 months (4 cycles, 28 days each).

Exploratory Translational Objectives for Both Study Parts:

• To estimate progression free survival (PFS) per investigator assessment using RECIST v1.1 for subjects who received continuous GRN-300 and weekly paclitaxel x 3.
• Evaluate exploratory biomarkers of target engagement and treatment response

Inclusion Criteria:

• Age ≥ 18 years.
• Part 1 dose-escalation cohorts: Diagnosis of persistent or recurrent, locally non-resectable or metastatic ovarian, primary peritoneal or fallopian tube epithelial cancer, or advanced solid tumors of any other histology who have progressed on standard therapy and for whom no further effective therapy is available
• Part 1 dose-expansion cohort / Part 2 dose-escalation cohorts / Part 2 dose-expansion cohort: Diagnosis of persistent or recurrent, locally non-resectable or metastatic ovarian, primary peritoneal or fallopian tube epithelial cancer who have progressed on standard therapy and for whom no further effective therapy is available. Patients with advanced solid tumors of any other histology will not be eligible to be enrolled in these cohorts.
• Part 2 dose-escalation cohorts / Part 2 dose-expansion cohort: paclitaxel treatment for the tumor should be indicated
• Histologic or cytologic confirmation of the original tumor by Pathology assessment is required.
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension, as defined by RECIST 1.1.
• Prior therapy: Patients must have received at least one prior second-line treatment for persistent, recurrent, locally non-resectable or metastatic disease but may have received any number of prior treatments.
• Any unresolved toxicities from prior therapy should be no greater than NCI-CTCAE v5.0 Grade 1 at screening.
• Patients who are expected to survive a minimum of three months after the first administration of the study drug.
• Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0-1.
• Adequate bone marrow, liver and renal function.

Exclusion Criteria:

• Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug.
• Patients with known hypersensitivity to paclitaxel excluded from Part 2 paclitaxel combination only).
• Use of any cytotoxic chemotherapy or investigational drugs, biologics, or devices within 21 days prior to study enrollment.
• Women who are pregnant or breastfeeding.
• Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection requiring treatment with antiviral therapy.
• Known CNS metastases or leptomeningeal disease.
• Gastrointestinal dysfunction that may affect oral drug absorption (e.g., intermittent or chronic bowel obstruction, short gut, etc.).
• Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within six months of start of study treatment.
• Other medical co-morbidities that in the investigator's judgment would increase the risks of participation
• QTc >480 msec be excluded from the study