Tucatinib Plus Trastuzumab and Oxaliplatin-based Chemotherapy or Pembrolizumab-containing Combinations for HER2+ Gastrointestinal Cancers

Study Overview
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Brief Summary
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This trial studies tucatinib to find out if it is safe when given with trastuzumab and other anti-cancer drugs (pembrolizumab, FOLFOX, and CAPOX). It will look at what side effects happen when participants take this combination of drugs. A side effect is anything the drug does other than treating cancer. It will also look at whether tucatinib works with these drugs to treat certain types of cancer. The participants in this trial have HER2-positive (HER2+) cancer in their gut, stomach, intestines, or gallbladder (gastrointestinal cancer).

Official Title
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A Phase 1b/2 Dose Escalation and Expansion Study of Tucatinib in Combination With Trastuzumab and Oxaliplatin-based Chemotherapy or Pembrolizumab-containing Combinations for HER2+ Gastrointestinal Cancers

Conditions
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Colorectal Carcinoma, Gastric Adenocarcinoma, GEJ Adenocarcinoma, Esophageal Adenocarcinoma, Cholangiocarcinoma, Gallbladder Carcinoma

Intervention / Treatment
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* Drug: tucatinib
* Drug: trastuzumab
* Drug: oxaliplatin
* Drug: leucovorin
* Drug: fluorouracil
* Drug: capecitabine
* Drug: pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have an unresectable or metastatic solid malignancy that is histologically or cytologically confirmed to be one of the tumor types listed below: Cohorts 1A, 1B, 1C, and 1D CRC Gastric adenocarcinoma GEJ adenocarcinoma Esophageal adenocarcinoma Cholangiocarcinoma Gallbladder carcinoma Cohorts 1E, 1F, 1G, and 2A Gastric adenocarcinoma GEJ adenocarcinoma Esophageal adenocarcinoma Cohort 2B CRC Participants must be candidates to receive an oxaliplatin-based regimen as part of their standard-of-care treatment for all cohorts, except Cohort 1G. HER2+ disease, as determined by historic or local laboratory testing Phase 1b cohorts: measurable or non-measurable disease according to RECIST v1.1 as determined by the investigator Phase 2 cohorts: measurable disease according to RECIST v1.1 as determined by the investigator Eastern Cooperative Oncology Group Performance Status score of 0 or 1. Exclusion Criteria: History of known hypersensitivity to planned study treatment Known to be positive for Hepatitis B or C For Cohorts 2A and 2B: prior anti-HER2 therapies For Cohorts 1E, 1F, 1G, 2A: Prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137), and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE) There are additional inclusion criteria. The study center will determine if criteria for participations are met.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1A<br>Tucatinib + trastuzumab + FOLFOX given in 14-day cycles | Drug: tucatinib<br>* For Cohort 1A, 150 mg will be administered twice daily by mouth (orally) from Cycle 1 Day 8 onwards. For all other cohorts, 300 mg (or intermediate dose) will be given orally twice daily starting on Cycle 1 Day 1.<br>* Other names: TUKYSA;Drug: trastuzumab<br>* Cohorts 1A and 1B: a 6 mg/kg loading dose will be given into the vein (IV; intravenously) on Cycle 1 Day 1, followed by a dose of 4 mg/kg IV every 2 weeks starting on Cycle 2 Day 1. Cohorts 1C, 1D, 1E, 1F, 1G, 2A, and 2B: an 8 mg/kg loading dose will be administered IV on Cycle 1 Day 1, followed by a dose of 6 mg/kg IV every 3 weeks thereafter.<br>Drug: oxaliplatin<br>* 85 mg/m^2 given IV every 2 weeks for cohorts using FOLFOX. For cohorts using CAPOX regimen, 130 mg/m^2 given every 3 weeks.<br>Drug: leucovorin<br>* 200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m^2 given IV every 2 weeks. Part of FOLFOX regimen.<br>Drug: fluorouracil<br>* 400 mg/m^2 (IV bolus after leucovorin) and/or 2400 mg/m^2 (continuous infusion over 46 hours). Part of FOLFOX regimen.<br>|
| Experimental: Cohort 1B<br>Tucatinib + trastuzumab + FOLFOX given in 14-day cycles | Drug: tucatinib<br>* For Cohort 1A, 150 mg will be administered twice daily by mouth (orally) from Cycle 1 Day 8 onwards. For all other cohorts, 300 mg (or intermediate dose) will be given orally twice daily starting on Cycle 1 Day 1.<br>* Other names: TUKYSA;Drug: trastuzumab<br>* Cohorts 1A and 1B: a 6 mg/kg loading dose will be given into the vein (IV; intravenously) on Cycle 1 Day 1, followed by a dose of 4 mg/kg IV every 2 weeks starting on Cycle 2 Day 1. Cohorts 1C, 1D, 1E, 1F, 1G, 2A, and 2B: an 8 mg/kg loading dose will be administered IV on Cycle 1 Day 1, followed by a dose of 6 mg/kg IV every 3 weeks thereafter.<br>Drug: oxaliplatin<br>* 85 mg/m^2 given IV every 2 weeks for cohorts using FOLFOX. For cohorts using CAPOX regimen, 130 mg/m^2 given every 3 weeks.<br>Drug: leucovorin<br>* 200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m^2 given IV every 2 weeks. Part of FOLFOX regimen.<br>Drug: fluorouracil<br>* 400 mg/m^2 (IV bolus after leucovorin) and/or 2400 mg/m^2 (continuous infusion over 46 hours). Part of FOLFOX regimen.<br>|
| Experimental: Cohort 1C<br>Tucatinib + trastuzumab + CAPOX given in 21-day cycles | Drug: tucatinib<br>* For Cohort 1A, 150 mg will be administered twice daily by mouth (orally) from Cycle 1 Day 8 onwards. For all other cohorts, 300 mg (or intermediate dose) will be given orally twice daily starting on Cycle 1 Day 1.<br>* Other names: TUKYSA;Drug: trastuzumab<br>* Cohorts 1A and 1B: a 6 mg/kg loading dose will be given into the vein (IV; intravenously) on Cycle 1 Day 1, followed by a dose of 4 mg/kg IV every 2 weeks starting on Cycle 2 Day 1. Cohorts 1C, 1D, 1E, 1F, 1G, 2A, and 2B: an 8 mg/kg loading dose will be administered IV on Cycle 1 Day 1, followed by a dose of 6 mg/kg IV every 3 weeks thereafter.<br>Drug: oxaliplatin<br>* 85 mg/m^2 given IV every 2 weeks for cohorts using FOLFOX. For cohorts using CAPOX regimen, 130 mg/m^2 given every 3 weeks.<br>Drug: capecitabine<br>* 1000 mg/m^2 is taken twice per day orally on Days 1-14 of each 3 week cycle. Part of CAPOX regimen.<br>|
| Experimental: Cohort 1D<br>Tucatinib + trastuzumab + FOLFOX. Tucatinib and FOLFOX given in 14-day cycles and trastuzumab given every 21 days | Drug: tucatinib<br>* For Cohort 1A, 150 mg will be administered twice daily by mouth (orally) from Cycle 1 Day 8 onwards. For all other cohorts, 300 mg (or intermediate dose) will be given orally twice daily starting on Cycle 1 Day 1.<br>* Other names: TUKYSA;Drug: trastuzumab<br>* Cohorts 1A and 1B: a 6 mg/kg loading dose will be given into the vein (IV; intravenously) on Cycle 1 Day 1, followed by a dose of 4 mg/kg IV every 2 weeks starting on Cycle 2 Day 1. Cohorts 1C, 1D, 1E, 1F, 1G, 2A, and 2B: an 8 mg/kg loading dose will be administered IV on Cycle 1 Day 1, followed by a dose of 6 mg/kg IV every 3 weeks thereafter.<br>Drug: oxaliplatin<br>* 85 mg/m^2 given IV every 2 weeks for cohorts using FOLFOX. For cohorts using CAPOX regimen, 130 mg/m^2 given every 3 weeks.<br>Drug: leucovorin<br>* 200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m^2 given IV every 2 weeks. Part of FOLFOX regimen.<br>Drug: fluorouracil<br>* 400 mg/m^2 (IV bolus after leucovorin) and/or 2400 mg/m^2 (continuous infusion over 46 hours). Part of FOLFOX regimen.<br>|
| Experimental: Cohort 1E<br>Tucatinib + trastuzumab + pembrolizumab + FOLFOX. Tucatinib and FOLFOX given in 14-day cycles, trastuzumab given in 21-day cycles, and pembrolizumab given in 42-day cycles | Drug: tucatinib<br>* For Cohort 1A, 150 mg will be administered twice daily by mouth (orally) from Cycle 1 Day 8 onwards. For all other cohorts, 300 mg (or intermediate dose) will be given orally twice daily starting on Cycle 1 Day 1.<br>* Other names: TUKYSA;Drug: trastuzumab<br>* Cohorts 1A and 1B: a 6 mg/kg loading dose will be given into the vein (IV; intravenously) on Cycle 1 Day 1, followed by a dose of 4 mg/kg IV every 2 weeks starting on Cycle 2 Day 1. Cohorts 1C, 1D, 1E, 1F, 1G, 2A, and 2B: an 8 mg/kg loading dose will be administered IV on Cycle 1 Day 1, followed by a dose of 6 mg/kg IV every 3 weeks thereafter.<br>Drug: oxaliplatin<br>* 85 mg/m^2 given IV every 2 weeks for cohorts using FOLFOX. For cohorts using CAPOX regimen, 130 mg/m^2 given every 3 weeks.<br>Drug: leucovorin<br>* 200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m^2 given IV every 2 weeks. Part of FOLFOX regimen.<br>Drug: fluorouracil<br>* 400 mg/m^2 (IV bolus after leucovorin) and/or 2400 mg/m^2 (continuous infusion over 46 hours). Part of FOLFOX regimen.<br>Drug: pembrolizumab<br>* 400 mg given by IV on day 1 of cycle 1, then every 6 weeks.<br>* Other names: KEYTRUDA;|
| Experimental: Cohort 1F<br>Tucatinib + trastuzumab + pembrolizumab + CAPOX. Tucatinib, trastuzumab, and CAPOX given in 21-day cycles and pembrolizumab given in 42-day cycles. | Drug: tucatinib<br>* For Cohort 1A, 150 mg will be administered twice daily by mouth (orally) from Cycle 1 Day 8 onwards. For all other cohorts, 300 mg (or intermediate dose) will be given orally twice daily starting on Cycle 1 Day 1.<br>* Other names: TUKYSA;Drug: trastuzumab<br>* Cohorts 1A and 1B: a 6 mg/kg loading dose will be given into the vein (IV; intravenously) on Cycle 1 Day 1, followed by a dose of 4 mg/kg IV every 2 weeks starting on Cycle 2 Day 1. Cohorts 1C, 1D, 1E, 1F, 1G, 2A, and 2B: an 8 mg/kg loading dose will be administered IV on Cycle 1 Day 1, followed by a dose of 6 mg/kg IV every 3 weeks thereafter.<br>Drug: oxaliplatin<br>* 85 mg/m^2 given IV every 2 weeks for cohorts using FOLFOX. For cohorts using CAPOX regimen, 130 mg/m^2 given every 3 weeks.<br>Drug: capecitabine<br>* 1000 mg/m^2 is taken twice per day orally on Days 1-14 of each 3 week cycle. Part of CAPOX regimen.<br>Drug: pembrolizumab<br>* 400 mg given by IV on day 1 of cycle 1, then every 6 weeks.<br>* Other names: KEYTRUDA;|
| Experimental: Cohort 1G<br>Tucatinib + trastuzumab + pembrolizumab. Tucatinib and trastuzumab given in 21-day cycles and pembrolizumab given in 42-day cycles. | Drug: tucatinib<br>* For Cohort 1A, 150 mg will be administered twice daily by mouth (orally) from Cycle 1 Day 8 onwards. For all other cohorts, 300 mg (or intermediate dose) will be given orally twice daily starting on Cycle 1 Day 1.<br>* Other names: TUKYSA;Drug: trastuzumab<br>* Cohorts 1A and 1B: a 6 mg/kg loading dose will be given into the vein (IV; intravenously) on Cycle 1 Day 1, followed by a dose of 4 mg/kg IV every 2 weeks starting on Cycle 2 Day 1. Cohorts 1C, 1D, 1E, 1F, 1G, 2A, and 2B: an 8 mg/kg loading dose will be administered IV on Cycle 1 Day 1, followed by a dose of 6 mg/kg IV every 3 weeks thereafter.<br>Drug: pembrolizumab<br>* 400 mg given by IV on day 1 of cycle 1, then every 6 weeks.<br>* Other names: KEYTRUDA;|
| Experimental: Cohort 2A<br>Tucatinib + trastuzumab + pembrolizumab + (FOLFOX or CAPOX). Either (1) tucatinib and FOLFOX given in 14-day cycles or (2) tucatinib and CAPOX given in 21-day cycles. Trastuzumab given in 21-day cycles and pembrolizumab given in 42-day cycles. | Drug: tucatinib<br>* For Cohort 1A, 150 mg will be administered twice daily by mouth (orally) from Cycle 1 Day 8 onwards. For all other cohorts, 300 mg (or intermediate dose) will be given orally twice daily starting on Cycle 1 Day 1.<br>* Other names: TUKYSA;Drug: trastuzumab<br>* Cohorts 1A and 1B: a 6 mg/kg loading dose will be given into the vein (IV; intravenously) on Cycle 1 Day 1, followed by a dose of 4 mg/kg IV every 2 weeks starting on Cycle 2 Day 1. Cohorts 1C, 1D, 1E, 1F, 1G, 2A, and 2B: an 8 mg/kg loading dose will be administered IV on Cycle 1 Day 1, followed by a dose of 6 mg/kg IV every 3 weeks thereafter.<br>Drug: oxaliplatin<br>* 85 mg/m^2 given IV every 2 weeks for cohorts using FOLFOX. For cohorts using CAPOX regimen, 130 mg/m^2 given every 3 weeks.<br>Drug: leucovorin<br>* 200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m^2 given IV every 2 weeks. Part of FOLFOX regimen.<br>Drug: fluorouracil<br>* 400 mg/m^2 (IV bolus after leucovorin) and/or 2400 mg/m^2 (continuous infusion over 46 hours). Part of FOLFOX regimen.<br>Drug: capecitabine<br>* 1000 mg/m^2 is taken twice per day orally on Days 1-14 of each 3 week cycle. Part of CAPOX regimen.<br>Drug: pembrolizumab<br>* 400 mg given by IV on day 1 of cycle 1, then every 6 weeks.<br>* Other names: KEYTRUDA;|
| Experimental: Cohort 2B<br>Tucatinib + trastuzumab + FOLFOX given in 14-day cycles. | Drug: tucatinib<br>* For Cohort 1A, 150 mg will be administered twice daily by mouth (orally) from Cycle 1 Day 8 onwards. For all other cohorts, 300 mg (or intermediate dose) will be given orally twice daily starting on Cycle 1 Day 1.<br>* Other names: TUKYSA;Drug: trastuzumab<br>* Cohorts 1A and 1B: a 6 mg/kg loading dose will be given into the vein (IV; intravenously) on Cycle 1 Day 1, followed by a dose of 4 mg/kg IV every 2 weeks starting on Cycle 2 Day 1. Cohorts 1C, 1D, 1E, 1F, 1G, 2A, and 2B: an 8 mg/kg loading dose will be administered IV on Cycle 1 Day 1, followed by a dose of 6 mg/kg IV every 3 weeks thereafter.<br>Drug: oxaliplatin<br>* 85 mg/m^2 given IV every 2 weeks for cohorts using FOLFOX. For cohorts using CAPOX regimen, 130 mg/m^2 given every 3 weeks.<br>Drug: leucovorin<br>* 200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m^2 given IV every 2 weeks. Part of FOLFOX regimen.<br>Drug: fluorouracil<br>* 400 mg/m^2 (IV bolus after leucovorin) and/or 2400 mg/m^2 (continuous infusion over 46 hours). Part of FOLFOX regimen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of renal dose-limiting toxicities (DLTs) (Cohorts 1A and 1B) |  | Up to one month; 2 cycles after receiving all study treatment (each cycle is 14 days) | 
| Incidence of adverse events (AEs) (Cohorts 1C, 1D, 1E, 1F, 1G, 2A, and 2B) | An AE is defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. | Up to approximately 12 months | 
| Incidence of laboratory abnormalities (Cohorts 1C, 1D, 1E, 1F, 1G, 2A, and 2B) |  | Up to approximately 12 months | 
| Incidence of DLTs (Cohorts 1C, 1D, 1E, 1F, and 1G) |  | Up to approximately 12 months | 
| Incidence of dose alterations (Cohort 1D) |  | Up to approximately 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of AEs (Cohorts 1A and 1B) | An AE is defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. | Up to approximately 12 months | 
| Incidence of laboratory abnormalities (Cohorts 1A and 1B) |  | Up to approximately 12 months | 
| Change in glomerular filtration rate (GFR) from baseline through 2 cycles of combination therapy (Cohorts 1A and 1B) | To be summarized using descriptive statistics | Up to approximately 6 weeks | 
| Pharmacokinetic (PK) parameter of tucatinib - AUClast (Cohorts 1A and 1B) | To be summarized using descriptive statistics | Up to approximately 2.5 months; through predose of Cycle 2, Day 1 (each cycle is 14 days) | 
| PK parameter of tucatinib - Cmax (Cohorts 1A and 1B) | To be summarized using descriptive statistics | Up to approximately 2.5 months; through predose of Cycle 2, Day 1 (each cycle is 14 days) | 
| PK parameter of tucatinib - Ctrough (Cohorts 1A, 1B, 1C, 1E, 1F, and 1G) | To be summarized using descriptive statistics | Up to approximately 2.5 months; through predose of Cycle 6, Day 1 | 
| PK parameter of tucatinib - Tmax (Cohorts 1A and 1B) | To be summarized using descriptive statistics | Up to approximately 2.5 months; through predose of Cycle 2, Day 1 (each cycle is 14 days) | 
| PK parameter of oxaliplatin - AUClast (Cohorts 1A and 1B) | To be summarized using descriptive statistics | Up to 15 days; through Cycle 2, Day 1 (each cycle is 14 days) | 
| PK parameter of oxaliplatin - Cmax (Cohorts 1A and 1B) | To be summarized using descriptive statistics | Up to 15 days; through Cycle 2, Day 1 (each cycle is 14 days) | 
| PK parameter of oxaliplatin - Tmax (Cohorts 1A and 1B) | To be summarized using descriptive statistics | Up to 15 days; through Cycle 2, Day 1 (each cycle is 14 days) | 
| Confirmed objective response rate (cORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 per investigator assessment (INV) (Cohort 2A) | cORR is defined as the proportion of participants with confirmed complete response (CR) or partial response (PR) | Up to approximately 2.5 years | 
| Duration of response (DOR) according to RECIST v1.1 per INV (Cohorts 1C, 1E, 1F, 1G, and 2A) | DOR is defined as the time from first documentation of objective response of confirmed CR or confirmed PR to the first documentation of disease progression or death from any cause, whichever occurs first. | Up to approximately 2.5 years | 
| Progression-free survival (PFS) according to RECIST v1.1 per INV (Cohorts 1C, 1E, 1F, 1G, and 2A) | PFS is defined as the time from the date of treatment initiation to the date of disease progression or death from any cause, which occurs first. | Up to approximately 2.5 years | 
| Overall survival (OS) (Cohort 1C, 1E, 1F, 1G, and 2A) | OS is defined as the time from treatment initiation to death due to any cause | Up to approximately 2.5 years | 
| Objective response rate (ORR) (Cohorts 1C, 1E, 1F, and 1G) | ORR is defined as the proportion of subjects with confirmed CR or PR, according to RECIST v1.1. | Up to approximately 2.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2+, HER2-positive, CRC, Gastric cancer, Esophageal cancer, Seattle Genetics