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

Sponsor

Seagen Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04430738

Collaborator

(none)

120

Enrollment

Locations

Arms

61.5

Anticipated Duration (Months)

6.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Colorectal Carcinoma Gastric Adenocarcinoma GEJ Adenocarcinoma Esophageal Adenocarcinoma Cholangiocarcinoma Gallbladder Carcinoma	Drug: tucatinib Drug: trastuzumab Drug: oxaliplatin Drug: leucovorin Drug: fluorouracil Drug: capecitabine Drug: pembrolizumab	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 15, 2020

Anticipated Primary Completion Date :

May 30, 2024

Anticipated Study Completion Date :

Oct 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1A Tucatinib + trastuzumab + FOLFOX given in 14-day cycles	Drug: tucatinib 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. Other Names: TUKYSA Drug: trastuzumab 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. Drug: oxaliplatin 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. Drug: leucovorin 200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m^2 given IV every 2 weeks. Part of FOLFOX regimen. Drug: fluorouracil 400 mg/m^2 (IV bolus after leucovorin) and/or 2400 mg/m^2 (continuous infusion over 46 hours). Part of FOLFOX regimen.
Experimental: Cohort 1B Tucatinib + trastuzumab + FOLFOX given in 14-day cycles	Drug: tucatinib 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. Other Names: TUKYSA Drug: trastuzumab 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. Drug: oxaliplatin 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. Drug: leucovorin 200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m^2 given IV every 2 weeks. Part of FOLFOX regimen. Drug: fluorouracil 400 mg/m^2 (IV bolus after leucovorin) and/or 2400 mg/m^2 (continuous infusion over 46 hours). Part of FOLFOX regimen.
Experimental: Cohort 1C Tucatinib + trastuzumab + CAPOX given in 21-day cycles	Drug: tucatinib 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. Other Names: TUKYSA Drug: trastuzumab 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. Drug: oxaliplatin 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. Drug: capecitabine 1000 mg/m^2 is taken twice per day orally on Days 1-14 of each 3 week cycle. Part of CAPOX regimen.
Experimental: Cohort 1D Tucatinib + trastuzumab + FOLFOX. Tucatinib and FOLFOX given in 14-day cycles and trastuzumab given every 21 days	Drug: tucatinib 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. Other Names: TUKYSA Drug: trastuzumab 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. Drug: oxaliplatin 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. Drug: leucovorin 200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m^2 given IV every 2 weeks. Part of FOLFOX regimen. Drug: fluorouracil 400 mg/m^2 (IV bolus after leucovorin) and/or 2400 mg/m^2 (continuous infusion over 46 hours). Part of FOLFOX regimen.
Experimental: Cohort 1E 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 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. Other Names: TUKYSA Drug: trastuzumab 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. Drug: oxaliplatin 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. Drug: leucovorin 200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m^2 given IV every 2 weeks. Part of FOLFOX regimen. Drug: fluorouracil 400 mg/m^2 (IV bolus after leucovorin) and/or 2400 mg/m^2 (continuous infusion over 46 hours). Part of FOLFOX regimen. Drug: pembrolizumab 400 mg given by IV on day 1 of cycle 1, then every 6 weeks. Other Names: KEYTRUDA
Experimental: Cohort 1F Tucatinib + trastuzumab + pembrolizumab + CAPOX. Tucatinib, trastuzumab, and CAPOX given in 21-day cycles and pembrolizumab given in 42-day cycles.	Drug: tucatinib 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. Other Names: TUKYSA Drug: trastuzumab 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. Drug: oxaliplatin 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. Drug: capecitabine 1000 mg/m^2 is taken twice per day orally on Days 1-14 of each 3 week cycle. Part of CAPOX regimen. Drug: pembrolizumab 400 mg given by IV on day 1 of cycle 1, then every 6 weeks. Other Names: KEYTRUDA
Experimental: Cohort 1G Tucatinib + trastuzumab + pembrolizumab. Tucatinib and trastuzumab given in 21-day cycles and pembrolizumab given in 42-day cycles.	Drug: tucatinib 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. Other Names: TUKYSA Drug: trastuzumab 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. Drug: pembrolizumab 400 mg given by IV on day 1 of cycle 1, then every 6 weeks. Other Names: KEYTRUDA
Experimental: Cohort 2A 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 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. Other Names: TUKYSA Drug: trastuzumab 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. Drug: oxaliplatin 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. Drug: leucovorin 200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m^2 given IV every 2 weeks. Part of FOLFOX regimen. Drug: fluorouracil 400 mg/m^2 (IV bolus after leucovorin) and/or 2400 mg/m^2 (continuous infusion over 46 hours). Part of FOLFOX regimen. Drug: capecitabine 1000 mg/m^2 is taken twice per day orally on Days 1-14 of each 3 week cycle. Part of CAPOX regimen. Drug: pembrolizumab 400 mg given by IV on day 1 of cycle 1, then every 6 weeks. Other Names: KEYTRUDA
Experimental: Cohort 2B Tucatinib + trastuzumab + FOLFOX given in 14-day cycles.	Drug: tucatinib 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. Other Names: TUKYSA Drug: trastuzumab 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. Drug: oxaliplatin 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. Drug: leucovorin 200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m^2 given IV every 2 weeks. Part of FOLFOX regimen. Drug: fluorouracil 400 mg/m^2 (IV bolus after leucovorin) and/or 2400 mg/m^2 (continuous infusion over 46 hours). Part of FOLFOX regimen.

Outcome Measures

Primary Outcome Measures

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) [Up to approximately 12 months]
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.
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

Incidence of AEs (Cohorts 1A and 1B) [Up to approximately 12 months]
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.
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) [Up to approximately 6 weeks]
To be summarized using descriptive statistics
Pharmacokinetic (PK) parameter of tucatinib - AUClast (Cohorts 1A and 1B) [Up to approximately 2.5 months; through predose of Cycle 2, Day 1 (each cycle is 14 days)]
To be summarized using descriptive statistics
PK parameter of tucatinib - Cmax (Cohorts 1A and 1B) [Up to approximately 2.5 months; through predose of Cycle 2, Day 1 (each cycle is 14 days)]
To be summarized using descriptive statistics
PK parameter of tucatinib - Ctrough (Cohorts 1A, 1B, 1C, 1E, 1F, and 1G) [Up to approximately 2.5 months; through predose of Cycle 6, Day 1]
To be summarized using descriptive statistics
PK parameter of tucatinib - Tmax (Cohorts 1A and 1B) [Up to approximately 2.5 months; through predose of Cycle 2, Day 1 (each cycle is 14 days)]
To be summarized using descriptive statistics
PK parameter of oxaliplatin - AUClast (Cohorts 1A and 1B) [Up to 15 days; through Cycle 2, Day 1 (each cycle is 14 days)]
To be summarized using descriptive statistics
PK parameter of oxaliplatin - Cmax (Cohorts 1A and 1B) [Up to 15 days; through Cycle 2, Day 1 (each cycle is 14 days)]
To be summarized using descriptive statistics
PK parameter of oxaliplatin - Tmax (Cohorts 1A and 1B) [Up to 15 days; through Cycle 2, Day 1 (each cycle is 14 days)]
To be summarized using descriptive statistics
Confirmed objective response rate (cORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 per investigator assessment (INV) (Cohort 2A) [Up to approximately 2.5 years]
cORR is defined as the proportion of participants with confirmed complete response (CR) or partial response (PR)
Duration of response (DOR) according to RECIST v1.1 per INV (Cohorts 1C, 1E, 1F, 1G, and 2A) [Up to approximately 2.5 years]
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.
Progression-free survival (PFS) according to RECIST v1.1 per INV (Cohorts 1C, 1E, 1F, 1G, and 2A) [Up to approximately 2.5 years]
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.
Overall survival (OS) (Cohort 1C, 1E, 1F, 1G, and 2A) [Up to approximately 2.5 years]
OS is defined as the time from treatment initiation to death due to any cause
Objective response rate (ORR) (Cohorts 1C, 1E, 1F, and 1G) [Up to approximately 2.5 years]
ORR is defined as the proportion of subjects with confirmed CR or PR, according to RECIST v1.1.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Arizona	Phoenix	Arizona	United States	85054
2	Stanford University School of Medicine	Stanford	California	United States	94305
3	University of Colorado Hospital / University of Colorado	Aurora	Colorado	United States	80045
4	SCL Health Good Samaritan Medical Center Cancer Centers of Colorado	Lafayette	Colorado	United States	80026
5	Johns Hopkins Medical Center	Washington	District of Columbia	United States	20016
6	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
7	University of Chicago Medical Center	Chicago	Illinois	United States	60637-1470
8	Mayo Clinic Rochester	Rochester	Minnesota	United States	55903-4008
9	Washington University in St Louis	Saint Louis	Missouri	United States	63110
10	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87131
11	Duke University Medical Center	Durham	North Carolina	United States	27710
12	Gabrail Cancer Center Research, LLC	Canton	Ohio	United States	44718
13	Cleveland Clinic, The	Cleveland	Ohio	United States	44195
14	Seattle Cancer Care Alliance / University of Washington	Seattle	Washington	United States	98109-1023
15	National Cancer Center Hospital	Chuo-ku	Other	Japan	104-0045
16	St. Marianna University School of Medicine	Kawasaki-shi	Other	Japan	2168511
17	Aichi Cancer Center	Nagoya-shi	Other	Japan	464-8681
18	Osaka International Cancer Institute	Osaka	Other	Japan	541-8567