GB1275 Monotherapy and in Combination With an Anti-PD1 Antibody in Patients With Specified Advanced Solid Tumors or in Combination With Standard of Care in Patients With Metastatic Pancreatic Adenocarcinoma

Study Overview
=================
Brief Summary
-----------------
This first-in-human (FIH ) study is an open-label, multicenter study that consists of a Phase 1 Dose Escalation/Expansion phase of GB1275 monotherapy or in combination with Anti-PD-1 Antibody or in combination with Standard of Care in Patients with Metastatic Pancreatic Adenocarcinoma followed by a Phase 2 Basket Expansion phase in Patients with Specified Metastatic Solid Tumors

Detailed Description
-----------------
Note: The Phase 2 portion of the study was not initiated.

Official Title
-----------------
A Phase 1/2, First-in-Human, Open-label, Dose Escalation Study of GB1275 Monotherapy and in Combination With an Anti-PD-1 Antibody in Patients With Specified Advanced Solid Tumors or in Combination With Standard of Care in Patients With Metastatic Pancreatic Adenocarcinoma, Followed by Basket Expansion of GB1275 With Standard of Care or in Combination With an Anti-PD-1 Antibody in Patients With Specified Metastatic Solid Tumors

Conditions
-----------------
Gastric Adenocarcinoma, Pancreatic Adenocarcinoma, Esophageal Adenocarcinoma, Esophageal Squamous Cell Carcinoma, Gastroesophageal Junction Adenocarcinoma, Triple Negative Breast Cancer, Castration-resistant Prostate Cancer, Microsatellite Stable Colorectal Cancer, Non-small Cell Lung Cancer, Small-cell Lung Cancer, Head and Neck Squamous Cell Carcinoma, Urothelial Carcinoma, Renal Cell Carcinoma, Hepatocellular Carcinoma

Intervention / Treatment
-----------------
* Drug: GB1275
* Drug: nab-paclitaxel and gemcitabine
* Drug: pembrolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. Women of childbearing potential must use an acceptable method of contraception Phase 1 Subjects with the the following: Regimen A and B: pancreatic adenocarcinoma, esophageal adenocarcinoma, or esophageal squamous cell carcinoma, or gastric/gastroesophageal junction adenocarcinoma, or TNBC, or prostate cancer, or colorectal adenocarcinoma, or subjects with tumor types that have progressed after receiving initial treatment benefit rom the last single agent checkpoint inhibitor that is approved for the indication or in combination with standard of care therapy, for example, non-small cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, renal cell carcinoma, and hepatocellular carcinoma, etc. Regimen C: newly diagnosed stage IV pancreatic cancer Phase 2 Cohort 1: pancreatic cancer. Cohort 2: colorectal cancer Cohort 3: gastric/GEJ adenocarcinoma Exclusion Criteria: History of another malignancy within 2 years prior to first study drug(s) administration, unless the malignancy was treated with curative intent and the likelihood of relapse is <5% in 2 years Pregnant or nursing Known history of testing positive for human immunodeficiency virus (HIV) Gastrointestinal (GI) tract disease causing the inability to take oral medication. Positive test for Hepatitis B virus surface antigen (HBsAg) or a and/or positive Hep C antibody result with detectable hepatitis C virus (HCV) ribonucleic acid (RNA) indicating acute or chronic infection. Other protocol-defined inclusion/exclusion criteria will apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1 - Dose Escalation of 3 different Regimens and Expansion, Phase 2 - Basket Expansion of 3 Cohorts
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Regimen A - GB1275 monotherapy<br>GB1275 Monotherapy dose escalation: Oral administration. Twice per day (BID). | Drug: GB1275<br>* Oral<br>* Other names: Investigational;|
| Experimental: Phase 1: Regimen B - GB1275 with an Anti-PD-1<br>GB1275 with pembrolizumab dose escalation and expansion: GB1275 oral administration; twice per day (BID), and pembrolizumab IV administration once every 3 weeks (Q3W). | Drug: GB1275<br>* Oral<br>* Other names: Investigational;Drug: pembrolizumab<br>* IV infusion<br>* Other names: Anti-PD-1;|
| Experimental: Phase 1: Regimen C - GB1275 with Standard of Care (SOC)<br>GB1275 with SOC dose escalation: GB1275 oral administration; twice per day (BID), and nab-paclitaxel and gemcitabine per United States Prescribing Information (USPI) | Drug: GB1275<br>* Oral<br>* Other names: Investigational;Drug: nab-paclitaxel and gemcitabine<br>* IV infusion<br>* Other names: Abraxane and Gemzar;|
| Experimental: Phase 2: Cohort 1 - GB1275 with SOC<br>GB1275 with SOC Basket Cohort in patients with newly diagnosed metastatic pancreatic cancer: GB1275 oral administration; twice per day (BID) and nab-paclitaxel and gemcitabine per USPI. | Drug: GB1275<br>* Oral<br>* Other names: Investigational;Drug: nab-paclitaxel and gemcitabine<br>* IV infusion<br>* Other names: Abraxane and Gemzar;|
| Experimental: Phase 2: Cohort 2 - GB1275 with an Anti-PD-1<br>GB1275 with pembrolizumab Basket Cohort in patients with MSS colorectal cancer: GB1275 oral administration; twice per day (BID), and pembrolizumab IV administration once every 3 weeks (Q3W). | Drug: GB1275<br>* Oral<br>* Other names: Investigational;Drug: pembrolizumab<br>* IV infusion<br>* Other names: Anti-PD-1;|
| Experimental: Phase 2: Cohort 3 - GB1275 with an Anti-PD-1<br>GB1275 with pembrolizumab Basket Cohort in patients with gastric/GEJ cancer, PD-L1 positive: GB1275 oral administration; twice per day (BID), and pembrolizumab IV administration once every 3 weeks (Q3W). | Drug: GB1275<br>* Oral<br>* Other names: Investigational;Drug: pembrolizumab<br>* IV infusion<br>* Other names: Anti-PD-1;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 Dose Escalation - Regimens A, B,and C: Incidence of dose limiting toxicities (DLTs) |  | Regimen A and B dose escalation Days 1-21, Regimen C dose escalation Days 8-36 days | 
| Phase 1 Dose Escalation - Regimens A, B, and C and Phase 1 Expansion - Regimen B: Incidence of adverse events (AEs) |  | Regimen A and C from first dose through 30 days post last dose, Regimen B from first dose through 90 days post last dose | 
| Phase 1 Dose Escalation - Regimens A and B: Cmax of GB1275 | Maximum observed plasma concentration | From first dose through 30 days post last dose | 
| Phase 1 Dose Escalation - Regimens A and B: Ctrough of GB1275 | Trough observed plasma concentration | From first dose through 30 days post last dose | 
| Phase 1 Dose Escalation - Regimens A and B: Tmax of GB1275 | Time of maximum observed plasma concentration | From first dose through 30 days post last dose | 
| Phase 1 Dose Escalation - Regimens A and B: t1/2 of GB1275 | Terminal phase elimination half-life | From first dose through 30 days post last dose | 
| Phase 1 Dose Escalation - Regimens A and B: AUC of GB1275 | Area under the plasma concentration-time curve | From first dose through 30 days post last dose | 
| Phase 1 Dose Escalation - Regimens A and B: CL/F of GB1275 | Oral clearance | From first dose through 30 days post last dose | 
| Phase 2 - Basket Cohorts 1, 2 and 3: Objective Response Rate (ORR) | ORR defined as the proportion of subjects with best overall confirmed response (BOCR) of either a complete response (CR) or partial response (PR) as assessed by the Investigator based on RECIST v1.1 | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 - Regimen C and Phase 1 Expansion - Regimen B: Cmax of GB1275 | Maximum observed plasma concentration | From first dose through 30 days post last dose | 
| Phase 1 - Regimen C and Phase 1 Expansion - Regimen B: Ctrough of GB1275 | Trough observed plasma concentration | From first dose through 30 days post last dose | 
| Phase 1 - Regimen C and Phase 1 Expansion - Regimen B: Tmax of GB1275 | Time of maximum observed plasma concentration | From first dose through 30 days post last dose | 
| Phase 1 - Regimen C and Phase 1 Expansion - Regimen B: t1/2 of GB1275 | Terminal phase elimination half-life | From first dose through 30 days post last dose | 
| Phase 1 - Regimen C and Phase 1 Expansion - Regimen B: AUC of GB1275 | Area under the plasma concentration-time curve | From first dose through 30 days post last dose | 
| Phase 1 - Regimen C and Phase 1 Expansion - Regimen B: CL/F of GB1275 | Oral clearance | From first dose through 30 days post last dose | 
| Phase 1 - Regimen C: Cmax of nab-paclitaxel and gemcitabine | Maximum observed plasma concentration | From first dose through 30 days post last dose | 
| Phase 1 - Regimen C: Tmax of nab-paclitaxel and gemcitabine) | Time of maximum observed plasma concentration | From first dose through 30 days post last dose | 
| Phase 1 - Regimen C: AUC of nab-paclitaxel and gemcitabine | Area under the plasma concentration-time curve | From first dose through 30 days post last dose | 
| Phase 2 - Basket Cohorts 1, 2, and 3: Duration of Response (DOR) | DOR defined as time from date of objective response to first documented date of disease progression or death | 24 months | 
| Phase 2 - Basket Cohorts 1, 2, and 3: Time to Response (TTR) | TTR defined as time from first dose to first date of objective response | 24 months | 
| Phase 2 - Basket Cohorts 1, 2, and 3: Clinical Benefit Rate (CBR) | CBR defined as proportion of subjects with confirmed CR, PR, or stable disease (SD) at six months. | 6 months | 
| Phase 2 - Basket Cohorts 1, 2, and 3: Progression Free Survival (PFS) | PFS defined as time from first dose to first documented date of disease progression or death. | 24 months | 
| Phase 2 - Basket Cohorts 1, 2, and 3: Time to Progression (TTP) | TTP defined as time from first dose to first documented date of disease progression. | 24 months | 
| Phase 2 - Basket Cohorts 1, 2, and 3: Overall Survival (OS) | OS defined as time from first dose to date of death. | 24 months | 
| Phase 2 - Basket Cohorts 1, 2, and 3: Incidence of AEs |  | Basket Cohorts 1 from first dose through 30 days post last dose, Basket Cohorts 2 and 3 from first dose through 90 days post last dose. | 
| Phase 2 - Basket Cohort 1, 2 and 3: PK profile of GB1275 |  | Basket Cohorts 1, 2, and 3 from first dose through 30 days post last dose. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
GEJ adenocarcinoma, TNBC, MSS mCRC, PD-L1 + gastric cancer, PD-L1 positive gastric cancer, NSCLC, SCLC, newly diagnosed stage IV pancreatic adenocarcinoma, HCC, RCC, HNSCC, Transitional Cell Carcinoma