A Study of GRC 54276 in Participants With Advanced Solid Tumors and Lymphomas.

A Phase 1, Open Label First In Human Study Investigating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of HPK1 Inhibitor GRC 54276 Alone and in Combination With Anti-PD-1 Monoclonal Antibody Pembrolizumab or Anti-PD-L1 Atezolizumab in Subjects With Advanced Solid Tumors and Lymphomas.

This is first in human (FIH) study to a) evaluate the safety and tolerability profile of GRC54276, b) determine the maximum tolerated dose (MTD) and recommended Phase 2 doses (RP2D), and c) pharmacokinetic profile of GRC54276 alone and in combination with pembrolizumab or atezolizumab in participants with advanced solid tumors and lymphomas.

Study Overview

• Status: Recruiting
• Conditions: Lymphoma; Advanced Solid Tumor
• Intervention / Treatment: Drug: GRC 54276; Drug: GRC 54276 + Pembrolizumab; Drug: GRC 54276 + Atezolizumab

• Study Type: Interventional
• Enrollment (Estimated): 320
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jatin Kadam; Phone Number: 02250451200; Email: clinicaltrialsdisclosuredesk@glenmarkpharma.com

Study Locations

• India
  • Delhi, India, 110017
    • Not yet recruiting
    • Max Superspeciality Hospital
  • Andhra Pradesh
    • Vijayawada, Andhra Pradesh, India, 520002
      • Recruiting
      • HCG City Cancer Centre
    • Visakhapatnam, Andhra Pradesh, India, 530017
      • Recruiting
      • Mahatma Gandhi Cancer Hospital and Research Institute
  • Haryana
    • Gurgaon, Haryana, India, 122001
      • Recruiting
      • Artemis Hospital
  • Karnataka
    • Bangalore, Karnataka, India, 5600027
      • Recruiting
      • Health Care Global Enterprises Ltd (HCG)
    • Bangalore, Karnataka, India, 560066
      • Recruiting
      • Vydehi Hospital
    • Bengaluru, Karnataka, India, 560064
      • Recruiting
      • Cytecare Hospitals Pvt Ltd.
    • Bengaluru, Karnataka, India, 560092
      • Recruiting
      • Aster CMI Hospital
  • Kerala
    • Kannur, Kerala, India, 670103
      • Recruiting
      • Malabar Cancer Centre
  • Maharashtra
    • Aurangabad, Maharashtra, India, 431001
      • Recruiting
      • Krupamayi Hospitals
    • Mumbai, Maharashtra, India, 400052
      • Recruiting
      • PD Hinduja Hospital and Medical Research Centre
    • Nashik, Maharashtra, India, 422002
      • Recruiting
      • HCG Manavata Cancer Centre
    • Nashik, Maharashtra, India, 422009
      • Recruiting
      • Sankalp Hospital
    • Thāne, Maharashtra, India, 401107
      • Active, not recruiting
      • Bhaktivedanta Hospital and Research Institute
  • Telangana
    • Hyderabad, Telangana, India, 500034
      • Recruiting
      • Basavatarakam Indo American Cancer Hospital Research Institute
    • Hyderabad, Telangana, India, 500032
      • Recruiting
      • AIG Hospitals, (A unit of asian Institute of Gastroenterology)
• United States
  • North Carolina
    • Huntersville, North Carolina, United States, 28078
      • Recruiting
      • Carolina BioOncology Institute
      • Contact: John D. Powderly II, MD
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226-1222
      • Recruiting
      • Froedtert & Medical College of Wisconsin - Froedtert Hospital - Clinical Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subjects (≥18 years of age) with histologically or cytologically confirmed advanced, metastatic, unresectable solid tumors or lymphomas who have previously received standard systemic therapy or for whom treatment is not accessible, not tolerated or refused, have progressed after ≥1 of systemic therapies for recurrent/metastatic disease and who have not received prior therapy targeting HPK1.
2. At least 1 measurable lesion as defined per RECIST 1.1. The target lesion(s) selected have not been previously treated with local therapy or the target lesion(s) selected that are within the field of prior local therapy have subsequently progressed as defined by RECIST 1.1.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 measured within 72 hours of treatment.
4. Predicted life expectancy of ≥3 months.
5. Adequate organ function as indicated by the following laboratory values up to first dose of study drug: Hemoglobin ≥9.0 g/dL, Absolute neutrophil count ≥1.5 x 109/L, Serum total bilirubin ≤1.5 x ULN (<3 x ULN for participants with Gilbert syndrome), AST and ALT ≤2.5 x ULN (≤5 x ULNs for participants with hepatocellular carcinoma or liver metastases).
6. Adequate renal function as indicated by creatinine clearance of ≥60mL/min calculated using Cokroft-Gault method.
7. Adequate cardiac function, left ventricular ejection fraction (LVEF) of ≥50% as assessed by multi-gated acquisition (MUGA) or ultrasound/echocardiography (ECHO).
8. For Part 2, dose expansion cohorts inclusion criteria specific to tumor types will be updated after completion of Part 1.

Exclusion Criteria:

1. Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study drug or interpretation of subject safety or study results.
2. Subjects with uncontrolled or untreated brain metastasis or leptomeningeal disease. Subjects with equivocal findings or with confirmed brain metastases are eligible provided that they are asymptomatic and radiologically stable without the need for corticosteroid treatment for at least 4 weeks prior to the first dose of study drug(s)
3. Any active malignancy ≤2 years before the first dose of study drug(s) except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated with curative intent (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast)

4. Any condition that required systemic treatment with either corticosteroids (>10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤14 days before the first dose of study drug(s), with the following exceptions:

   1. Adrenal replacement steroid (dose ≤10 mg daily of prednisone or equivalent)
   2. Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with minimal systemic absorption
   3. Short course (≤7 days) of corticosteroid prescribed prophylactically (e.g., for contrast dye allergy) or for the treatment of a non-autoimmune condition (e.g., delayed-type hypersensitivity reaction caused by contact allergen)
5. Pregnant/planning to be pregnant or breast-feeding women.
6. Any important medical illness or abnormal laboratory finding that would increase the risk of participating in this study (based on the investigator's judgment).
7. Any known severe allergic reaction to pembrolizumab/atezolizumab or its excipients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GRC 54276	Drug: GRC 54276; Part 1a: GRC 54276 QD will be administered orally from Day 1 to Day 21 in a 21-day treatment cycle. Part 2: GRC 54276 monotherapy therapy will commence after establishment of the MTD and/or RP2D for monotherapy arm.
Experimental: GRC 54276 with pembrolizumab	Drug: GRC 54276 + Pembrolizumab; Part 1b: GRC 54276 QD will be administered orally in combination with fixed dose of pembrolizumab IV every 21 days. Part 2: GRC 54276 in combination with pembrolizumab will commence after establishment of the MTD and/or RP2D for combination therapy arm.
Experimental: GRC 54276 with atezolizumab	Drug: GRC 54276 + Atezolizumab; Part 1b: GRC 54276 QD will be administered orally in combination with fixed dose of atezolizumab IV every 21 days. Part 2: GRC 54276 in combination with atezolizumab will commence after establishment of the MTD and/or RP2D for combination therapy arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicities to establish the maximum tolerated dose (MTD) and/or Recommended Phase 2 Dose (RP2D)	Percentage of participants with dose limiting toxicities associated with GRC54276 alone or GRC54276 combined with pembrolizumab or atezolizumab during the first cycle. Toxicity will be assessed using the NCI CTCAE Version 5.0.	18 weeks
Incidence of treatment-emergent adverse events and serious adverse events	Percentage of participants who experience treatment-emergent adverse events and serious adverse events when given GRC54276 as a single agent and in combination with pembrolizumab or atezolizumab.	up to 120 days
Changes in the laboratory safety values from baseline to end of safety follow-up	Percentage of participants who experience changes in the laboratory safety values when given GRC54276 as a single agent and in combination with pembrolizumab or atezolizumab.	up to 120 days
Pharmacokinetic profile of GRC54276- Maximum plasma concentration (Cmax)	The maximum measured plasma concentration after single or multiple dosing, tabulated by dose group and day of dosing.	up to 22 days
Pharmacokinetic profile of GRC54276- Time to Cmax (Tmax)	The time to achieve Cmax after single or multiple dosing, tabulated by dose group and day of dosing.	up to 22 days
Pharmacokinetic profile of GRC54276- Area under the curve (AUC)	Area under plasma concentration versus time curve from time 0 to time of least measurable concentration or the dosing interval, tabulated by dose group and day of dosing.	up to 22 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	Proportion of participants with a best response of complete response or partial response best on RECIST 1.1.	up to 9 months
Best overall response rate	Complete response, partial response, stable disease, and progressive disease, evaluated according to RECIST 1.1.	up to 9 months
Disease control rate	The percentage of participants who have achieved stable disease or complete response or partial response according to RECIST 1.1. for the entire duration of the study.	up to 9 months
Duration of response	The time from first documentation of complete response or partial response to the first documentation of progression.	up to 9 months

Collaborators and Investigators

• Sponsor: Glenmark Specialty S.A.
• Investigators: Study Director: Harsha Doddihal, MD, Glenmark Pharmaceuticals Ltd.; Study Director: Adam Y-Beltran, MD, Glenmark Pharmaceuticals Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2022
• Primary Completion (Estimated): July 30, 2027
• Study Completion (Estimated): July 30, 2027

Study Registration Dates

• First Submitted: May 19, 2023
• First Submitted That Met QC Criteria: May 19, 2023
• First Posted (Actual): May 26, 2023

Study Record Updates

• Last Update Posted (Estimated): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Lymphoma; Solid tumor; MTD
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab; Atezolizumab
• Other Study ID Numbers: GRC 54276-101; CTRI/2022/05/042484 (Registry Identifier: Clinical Trials Registry-India)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No