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

NCT04430738 | Active Not Recruiting Phase 2 Results FDA Drug

• 2 other identifiers: SGNTUC-024C4251005
• Study Type: interventional
• Target: 40
• Locations: 2 countries
• Sites: 27

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).

Conditions

Gallbladder Carcinoma; Colorectal Carcinoma; Gastric Adenocarcinoma; GEJ Adenocarcinoma; Esophageal Adenocarcinoma; Cholangiocarcinoma

Keywords

HER2+; HER2-positive; CRC; Gastric cancer; Esophageal cancer; Seattle Genetics

Outcome Measures

Primary Outcomes (34)

• Number of Participants With Renal Dose-Limiting Toxicities (DLTs): Phase 1b (Cohort 1A and 1B)

  A renal DLT was defined as an increase in serum cystatin C \>1.5\* baseline that was not related to pre-renal or post-renal etiologies (including disease progression, dehydration and intercurrent illness) and occurred during the period of treatment with tucatinib in combination with trastuzumab and FOLFOX between the first dose of tucatinib and the end of Cycle 3. Increased serum cystatin C for which there was an alternative clinical explanation (eg, clearly related to an intercurrent illness or disease progression) was not considered renal DLTs.

  From first dose of tucatinib until end of Cycle 3 (up to 42 days)

• Number of Participants With Treatment Emergent Adverse Events (TEAEs): Phase 1b (Cohort 1E and 1F)

  An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

• Number of Participants With Treatment Related TEAEs: Phase 1b (Cohort 1E and 1F)

  An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment. Treatment related TEAEs were AEs related to any study treatment and relatedness was judged by investigator.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

• Number of Participants With Greater Than or Equal to (>=) Grade 3 TEAEs: Phase 1b (Cohort 1E and 1F)

  An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment. TEAEs were graded according to National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v) 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Number of participants with \>= grade 3 TEAEs are reported in this outcome measure.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

• Number of Participants With >= Grade 3 Treatment Related TEAEs: Phase 1b (Cohort 1E and 1F)

  An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator. Number of participants with \>= grade 3 treatment related TEAEs are reported in this outcome measure.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

• Number of Participants With Any Serious Adverse Event (SAE): Phase 1b (Cohort 1E and 1F)

  An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

• Number of Participants With Any Treatment Related SAE: Phase 1b (Cohort 1E and 1F)

  An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant. Treatment related SAEs were SAEs related to any study treatment and relatedness was judged by investigator.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

• Number of Participants With DLTs: Phase 1b (Cohort 1E)

  DLTs were AEs/ laboratory abnormalities that were considered to be related to tucatinib/ tucatinib in combination with chemotherapy(mFOLFOX6/CAPOX) and/or trastuzumab and/or pembrolizumab. DLTs was defined any of following: a-)Hepatic- any instance of aspartate aminotransferase(AST)/ alanine aminotransferase(ALT)\>3\*upper limit of normal(ULN) and total bilirubin \>2\*ULN that is not thought to be due to progressive disease(PD)/other medical illness. PD:at least 20% increase in sum of diameters of target lesions,taking as reference smallest sum on study. In addition to relative increase of 20%,sum must also demonstrate an absolute increase of at least 5 millimeters(mm). b-) Non-hematologic- any clinically significant, non-hematologic treatment-related AE\>= grade(G)3, with following exceptions:G3 fatigue=\< 7days,G3 diarrhea,nausea/vomiting without optimal use of anti-emetics/antidiarrheals c-)hematologic:\>=G3 febrile neutropenia and absolute neutrophil count(ANC) decreased G4 for \>7days.

  Cycle 1 (Up to 21 days)

• Number of Participants With DLTs: Phase 1b (Cohort 1F)

  DLTs were AEs/ laboratory abnormalities that were considered to be related to tucatinib/ tucatinib in combination with chemotherapy (mFOLFOX6/CAPOX) and/ or trastuzumab and/ or pembrolizumab. DLTs was defined any of following: a-) Hepatic- any instance of AST/ ALT \>3\*ULN and total bilirubin \>2\*ULN that is not thought to be due to PD/ other medical illness. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. b-) Non-hematologic- any clinically significant, non-hematologic treatment-related AE\>= grade 3, with following exceptions: grade 3 fatigue=\< 7days, grade 3 diarrhea, nausea/vomiting without optimal use of anti-emetics/antidiarrheals c-) hematologic: \>= grade 3 febrile neutropenia and ANC decreased grade 4 for \>7days.

  Cycle 1 (Up to 28 days)

• Number of Participants With Treatment Emergent Hematological Laboratory Abnormalities: Phase 1b (Cohort 1E and 1F)

  The following hematological parameters were assessed: hemoglobin decreased, leukocytes decreased, lymphocytes decreased, neutrophils decreased and platelets decreased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment. Hematological laboratory abnormalities were graded according to NCI CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with hematological abnormalities of any grade were reported.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

• Number of Participants With Treatment Emergent Chemistry Laboratory Abnormalities: Phase 1b (Cohort 1E and 1F)

  The following chemistry laboratory parameters were assessed: alanine aminotransferase (ALT) increased, albumin decreased, alkaline phosphatase increased, aspartate aminotransferase (AST) increased, calcium corrected for albumin decreased, creatinine increased, calcium corrected for albumin increased, lactate dehydrogenase increased, potassium decreased, potassium increased, sodium decreased, sodium increased and total bilirubin increased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment Chemistry laboratory abnormalities were graded according to NCI CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with chemistry abnormalities of any grade were reported.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

• Number of Participants With Clinically Significant Post-Baseline Vital Signs: Phase 1b (Cohort 1E and 1F)

  Vital signs included temperature, blood pressure, heart rate and respiratory rate. Clinically significant vital signs were defined as: temperature greater than or equal to (\>=) 38 degrees Celsius, respiratory rate greater than (\>) 20 breaths per minute, systolic blood pressure (SBP) \>= 120 millimeter of mercury (mmHg) or diastolic blood pressure (DBP) \>= 80 mmHg, SBP \>= 140 mmHg or DBP \>= 90 mmHg and heart rate \> 100 beats per minute (bpm).

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

• Number of Participants With TEAEs: Phase 1b (Cohort 1D)

  An AE was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

• Number of Participants With Treatment Related TEAEs: Phase 1b (Cohort 1D)

  An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

• Number of Participants With >= Grade 3 TEAEs: Phase 1b (Cohort 1D)

  An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Number of participants with \>= grade 3 TEAEs are reported in this outcome measure.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

• Number of Participants With >= Grade 3 Treatment Related TEAEs: Phase 1b (Cohort 1D)

  An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator. Number of participants with \>= grade 3 treatment related TEAEs are reported in this outcome measure.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

• Number of Participants With Any SAE: Phase 1b (Cohort 1D)

  An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

• Number of Participants With Any Treatment Related SAE: Phase 1b (Cohort 1D)

  An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant. Treatment related SAEs were SAEs related to any study treatment and relatedness was judged by investigator.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

• Number of Participants With DLTs: Phase 1b (Cohort 1D)

  DLTs were AEs/ laboratory abnormalities that were considered to be related to tucatinib/ tucatinib in combination with chemotherapy (mFOLFOX6/CAPOX) and/ or trastuzumab and/ or pembrolizumab. DLTs was defined any of following: a-) Hepatic- any instance of AST/ ALT \>3\*ULN and total bilirubin \>2\*ULN that is not thought to be due to PD/ other medical illness. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. b-) Non-hematologic- any clinically significant, non-hematologic treatment-related AE\>= grade 3, with following exceptions: grade 3 fatigue=\< 7days, grade 3 diarrhea, nausea/vomiting without optimal use of anti-emetics/antidiarrheals c-) hematologic: \>= grade 3 febrile neutropenia and ANC decreased grade 4 for \>7days.

  Cycle 1 (Up to 28 days)

• Number of Participants With Treatment Emergent Hematological Laboratory Abnormalities: Phase 1b (Cohort 1D)

  The following hematological parameters were assessed: hemoglobin decreased, leukocytes decreased, lymphocytes decreased, neutrophils decreased and platelets decreased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Hematological laboratory abnormalities were graded according to NCI CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with hematological abnormalities of any grade were reported.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

• Number of Participants With Treatment Emergent Chemistry Laboratory Abnormalities: Phase 1b (Cohort 1D)

  The following chemistry parameters were assessed: ALT increased, albumin decreased, alkaline phosphatase increased, AST increased, calcium corrected for albumin decreased, creatinine increased, lactate dehydrogenase increased, potassium decreased, potassium increased, sodium decreased and sodium increased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Chemistry laboratory parameters abnormalities were graded according to NCI CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with chemistry abnormalities of any grade were reported.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

• Number of Participants With Clinically Significant Post-Baseline Vital Signs: Phase 1b (Cohort 1D)

  Vital signs included temperature, blood pressure, heart rate and respiratory rate. Clinically significant vital signs were defined as: temperature \>= 38 degrees Celsius, respiratory rate \> 20 breaths per minute, SBP \>= 120 mmHg or DBP \>= 80 mmHg, SBP \>= 140 mmHg or DBP \>= 90 mmHg and heart rate \> 100 beats per minute (bpm).

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

• Number of Participants With TEAEs Leading to Dose Holds: Phase 1b (Cohort 1D)

  An AE was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Dose hold was considered as dose delay and dose elimination. Number of participants with TEAEs leading to dose holds are reported in this outcome measure.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

• Number of Participants With TEAEs Leading to Dose Reductions: Phase 1b (Cohort 1D)

  An AE was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Number of participants with TEAEs leading to dose reductions are reported in this outcome measure.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

• Number of Participants With TEAEs Leading to Dose Discontinuations: Phase 1b (Cohort 1D)

  An AE was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Number of participants with TEAEs leading to dose discontinuations (i.e. permanent withdrawal of tucatinib, trastuzumab, oxaliplatin, fluorouracil and leucovorin) are reported in this outcome measure.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

• Number of Participants With TEAEs: Phase 2 (Cohort 2B)

  An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

• Number of Participants With Treatment Related TEAEs: Phase 2 (Cohort 2B)

  An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

• Number of Participants With >= Grade 3 TEAEs: Phase 2 (Cohort 2B)

  An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Number of participants with \>= grade 3 TEAEs are reported in this outcome measure.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

• Number of Participants With >= Grade 3 Treatment Related TEAEs: Phase 2 (Cohort 2B)

  An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator. Number of participants with \>= grade 3 treatment related TEAEs are reported in this outcome measure.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

• Number of Participants With Any SAE: Phase 2 (Cohort 2B)

  An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

• Number of Participants With Any Treatment Related SAE: Phase 2 (Cohort 2B)

  An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant. Treatment related SAEs were SAEs related to any study treatment and relatedness was judged by investigator.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

• Number of Participants With Treatment Emergent Hematological Laboratory Abnormalities: Phase 2 (Cohort 2B)

  Following hematological parameters were assessed: hemoglobin decreased, leukocytes decreased, lymphocytes decreased, neutrophils decreased and platelets decreased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Hematological abnormalities were graded according to NCI CTCAE v 5.0; where, grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with hematologic abnormalities of any grade were reported.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

• Number of Participants With Treatment Emergent Chemistry Laboratory Abnormalities: Phase 2 (Cohort 2B)

  Following chemistry parameters were assessed: ALT increased, albumin decreased, alkaline phosphatase increased, AST increased, creatinine increased, glomerular filtration rate (GFR) estimated decreased, lactate dehydrogenase increased, potassium decreased, potassium increased, sodium decreased, sodium increased and total bilirubin increased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Chemistry abnormalities were graded according to NCI CTCAE v 5.0; where, grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Participants with chemistry abnormalities of any grade were reported.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

• Number of Participants With Clinically Significant Post-Baseline Vital Signs: Phase 2 (Cohort 2B)

  Vital signs included temperature, blood pressure and heart rate. Clinically significant vital signs were defined as: temperature \>= 38 degrees Celsius, respiratory rate \> 20 breaths per minute, SBP \>= 120 mmHg or DBP \>= 80 mmHg, SBP \>= 140 mmHg or DBP \>= 90 mmHg and heart rate \> 100 bpm.

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

Secondary Outcomes (26)

• Number of Participants With TEAEs: Phase 1b (Cohort 1A and 1B)

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

• Number of Participants With Treatment Related TEAEs: Phase 1b (Cohort 1A and 1B)

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

• Number of Participants With >= Grade 3 TEAEs: Phase 1b (Cohort 1A and 1B)

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

• Number of Participants With >= Grade 3 Treatment Related TEAEs: Phase 1b (Cohort 1A and 1B)

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

• Number of Participants With Any SAE: Phase 1b (Cohort 1A and 1B)

  From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

Study Arms (9)

Cohort 1A

EXPERIMENTAL

Tucatinib + trastuzumab + FOLFOX given in 14-day cycles

Drug: tucatinib; Drug: trastuzumab; Drug: oxaliplatin; Drug: leucovorin; Drug: fluorouracil

Cohort 1B

EXPERIMENTAL

Tucatinib + trastuzumab + FOLFOX given in 14-day cycles

Drug: tucatinib; Drug: trastuzumab; Drug: oxaliplatin; Drug: leucovorin; Drug: fluorouracil

Cohort 1C

EXPERIMENTAL

Tucatinib + trastuzumab + CAPOX given in 21-day cycles

Drug: tucatinib; Drug: trastuzumab; Drug: oxaliplatin; Drug: capecitabine

Cohort 1D

EXPERIMENTAL

Tucatinib + trastuzumab + FOLFOX. Tucatinib and FOLFOX given in 14-day cycles and trastuzumab given every 21 days

Drug: tucatinib; Drug: trastuzumab; Drug: oxaliplatin; Drug: leucovorin; Drug: fluorouracil

Cohort 1E

EXPERIMENTAL

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; Drug: trastuzumab; Drug: oxaliplatin; Drug: leucovorin; Drug: fluorouracil; Drug: pembrolizumab

Cohort 1F

EXPERIMENTAL

Tucatinib + trastuzumab + pembrolizumab + CAPOX. Tucatinib, trastuzumab, and CAPOX given in 21-day cycles and pembrolizumab given in 42-day cycles.

Drug: tucatinib; Drug: trastuzumab; Drug: oxaliplatin; Drug: capecitabine; Drug: pembrolizumab

Cohort 1G

EXPERIMENTAL

Tucatinib + trastuzumab + pembrolizumab. Tucatinib and trastuzumab given in 21-day cycles and pembrolizumab given in 42-day cycles.

Drug: tucatinib; Drug: trastuzumab; Drug: pembrolizumab

Cohort 2A

EXPERIMENTAL

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; Drug: trastuzumab; Drug: oxaliplatin; Drug: leucovorin; Drug: fluorouracil; Drug: capecitabine; Drug: pembrolizumab

Cohort 2B

EXPERIMENTAL

Tucatinib + trastuzumab + FOLFOX given in 14-day cycles.

Drug: tucatinib; Drug: trastuzumab; Drug: oxaliplatin; Drug: leucovorin; Drug: fluorouracil

Interventions

leucovorin DRUG

200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m\^2 given IV every 2 weeks. Part of FOLFOX regimen.

Cohort 1A; Cohort 1B; Cohort 1D; Cohort 1E; Cohort 2A; Cohort 2B

fluorouracil DRUG

400 mg/m\^2 (IV bolus after leucovorin) and/or 2400 mg/m\^2 (continuous infusion over 46 hours). Part of FOLFOX regimen.

Cohort 1A; Cohort 1B; Cohort 1D; Cohort 1E; Cohort 2A; Cohort 2B

capecitabine DRUG

1000 mg/m\^2 is taken twice per day orally on Days 1-14 of each 3 week cycle. Part of CAPOX regimen.

Cohort 1C; Cohort 1F; Cohort 2A

pembrolizumab DRUG

400 mg given by IV on day 1 of cycle 1, then every 6 weeks.

Also known as: KEYTRUDA

Cohort 1E; Cohort 1F; Cohort 1G; Cohort 2A

tucatinib DRUG

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.

Also known as: TUKYSA

Cohort 1A; Cohort 1B; Cohort 1C; Cohort 1D; Cohort 1E; Cohort 1F; Cohort 1G; Cohort 2A; Cohort 2B

trastuzumab DRUG

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.

Cohort 1A; Cohort 1B; Cohort 1C; Cohort 1D; Cohort 1E; Cohort 1F; Cohort 1G; Cohort 2A; Cohort 2B

oxaliplatin DRUG

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.

Cohort 1A; Cohort 1B; Cohort 1C; Cohort 1D; Cohort 1E; Cohort 1F; Cohort 2A; Cohort 2B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• Seagen, a wholly owned subsidiary of Pfizer: lead

Study Sites (27)

Mayo Clinic Hospital

Phoenix, Arizona, 85054, United States

Location

Mayo Clinic

Scottsdale, Arizona, 85259, United States

Location

University of Colorado Denver CTO(CTRC)

Aurora, Colorado, 80045, United States

Location

University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)

Aurora, Colorado, 80045, United States

Location

University of Colorado Hospital - Anschutz Inpatient Pavilion (AIP)

Aurora, Colorado, 80045, United States

Location

University of Colorado Hospital - Anschutz Outpatient Pavilion (AOP)

Aurora, Colorado, 80045, United States

Location

PCM Trials

Denver, Colorado, 80218, United States

Location

Sibley Memorial Hospital

Washington D.C., District of Columbia, 20016, United States

Location

Siteman Cancer Center - St Peters

City of Saint Peters, Missouri, 63376, United States

Location

Siteman Cancer Center - West County

Creve Coeur, Missouri, 63141, United States

Location

Siteman Cancer Center - North County

Florissant, Missouri, 63031, United States

Location

Siteman Cancer Center

St Louis, Missouri, 63108, United States

Location

Barnes-Jewish Hospital

St Louis, Missouri, 63110, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Siteman Cancer Center - South County

St Louis, Missouri, 63129, United States

Location

University of New Mexico Comprehensive Cancer Center

Albuquerque, New Mexico, 87131, United States

Location

Duke University Medical Center, Duke Cancer Center

Durham, North Carolina, 27710, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Fred Hutchinson Cancer Center

Seattle, Washington, 98109, United States

Location

University of Washington Medical Center

Seattle, Washington, 98195, United States

Location

Aichi Cancer Center Hospital

Nagoya, Aichi-ken, 464-8681, Japan

Location

National Cancer Center Hospital East

Kashiwa-shi, Chiba, 277-8577, Japan

Location

St. Marianna University Hospital

Kawasaki, Kanagawa, 216-8511, Japan

Location

Osaka International Cancer Institute

Osaka, Osaka, 541-8567, Japan

Location

National Cancer Center Hospital

Chuo-ku, Tokyo, 104-0045, Japan

Location

Cancer Institute Hospital of Japanese Foundation for Cancer Research.

Koto-ku, Tokyo, 135-8550, Japan

Location

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Colorectal Neoplasms; Adenocarcinoma Of Esophagus; Cholangiocarcinoma; Gallbladder Neoplasms; Stomach Neoplasms; Esophageal Neoplasms

Interventions

tucatinib; Trastuzumab; Oxaliplatin; Leucovorin; Fluorouracil; Capecitabine; pembrolizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Biliary Tract Neoplasms; Biliary Tract Diseases; Gallbladder Diseases; Stomach Diseases; Head and Neck Neoplasms; Esophageal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Coordination Complexes; Organic Chemicals; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

8007181021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 10, 2020
• First Posted: June 12, 2020
• Study Start: September 15, 2020
• Primary Completion: July 31, 2024
• Study Completion (Estimated): December 31, 2026
• Last Updated: February 24, 2026
• Results First Posted: September 9, 2025

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share

Locations

US (21); JP (6)