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Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer (MOUNTAINEER-02)

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ClinicalTrials.gov Identifier: NCT04499924
Recruitment Status : Not yet recruiting
First Posted : August 5, 2020
Last Update Posted : August 5, 2020
Sponsor:
Information provided by (Responsible Party):
Seattle Genetics, Inc.

Brief Summary:

This study is being done to see if tucatinib with trastuzumab, ramucirumab and paclitaxel works better than ramucirumab and paclitaxel to treat HER2-positive (HER2+) cancer of the gut (stomach or gastroesophageal cancer). This study will also 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.

Study treatment will be given in 28-day cycles.

In the Phase 2 part of the trial, participants and their doctors will know what drugs are being given (open-label). In the Phase 3 part, the study is "blinded." This means that participants, their doctor, and the study sponsor will not know which drugs are being given.


Condition or disease Intervention/treatment Phase
Gastric Adenocarcinoma Gastroesophageal Junction Adenocarcinoma Esophageal Adenocarcinoma Drug: tucatinib Drug: trastuzumab Drug: ramucirumab Drug: paclitaxel Other: tucatinib placebo Other: trastuzumab placebo Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 566 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Placebo-controlled, Active Comparator Phase 2/3 Study of Tucatinib in Combination With Trastuzumab, Ramucirumab, and Paclitaxel in Subjects With Previously Treated, Locally-advanced Unresectable or Metastatic HER2+ Gastric or Gastroesophageal Junction Adenocarcinoma (GEC)
Estimated Study Start Date : October 31, 2020
Estimated Primary Completion Date : May 31, 2025
Estimated Study Completion Date : March 31, 2027

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase 2 Arm
Tucatinib + trastuzumab + ramucirumab + paclitaxel
Drug: tucatinib
300 mg given twice daily orally
Other Name: TUKYSA, ONT-380, ARRY-380

Drug: trastuzumab
6 mg/kg loading dose will be administered intravenously (IV; into the vein) on Cycle 1 Day 1, followed by 4 mg/kg IV on Cycle 1 Day 15 and then Days 1 and 15 of each cycle thereafter

Drug: ramucirumab
8 mg/kg will be administered IV on Days 1 and 15 of each cycle
Other Name: CYRAMZA

Drug: paclitaxel
60 or 80 mg/m^2 IV on Days 1, 8, and 15 of each cycle

Experimental: Arm 3A
Tucatinib + trastuzumab + ramucirumab + paclitaxel
Drug: tucatinib
300 mg given twice daily orally
Other Name: TUKYSA, ONT-380, ARRY-380

Drug: trastuzumab
6 mg/kg loading dose will be administered intravenously (IV; into the vein) on Cycle 1 Day 1, followed by 4 mg/kg IV on Cycle 1 Day 15 and then Days 1 and 15 of each cycle thereafter

Drug: ramucirumab
8 mg/kg will be administered IV on Days 1 and 15 of each cycle
Other Name: CYRAMZA

Drug: paclitaxel
60 or 80 mg/m^2 IV on Days 1, 8, and 15 of each cycle

Active Comparator: Arm 3B
Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo
Drug: ramucirumab
8 mg/kg will be administered IV on Days 1 and 15 of each cycle
Other Name: CYRAMZA

Drug: paclitaxel
60 or 80 mg/m^2 IV on Days 1, 8, and 15 of each cycle

Other: tucatinib placebo
Given twice daily orally

Other: trastuzumab placebo
IV on Days 1 and 15 of each cycle

Experimental: Arm 3C
Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo
Drug: tucatinib
300 mg given twice daily orally
Other Name: TUKYSA, ONT-380, ARRY-380

Drug: ramucirumab
8 mg/kg will be administered IV on Days 1 and 15 of each cycle
Other Name: CYRAMZA

Drug: paclitaxel
60 or 80 mg/m^2 IV on Days 1, 8, and 15 of each cycle

Other: trastuzumab placebo
IV on Days 1 and 15 of each cycle




Primary Outcome Measures :
  1. Overall survival (OS) (Phase 3 only) [ Time Frame: 60 months ]
    OS is defined as the time from randomization to death due to any cause

  2. Progression-free survival (PFS) per RECIST version 1.1 according to investigator assessment (Phase 3 only) [ Time Frame: 36 months ]
    PFS is defined as the time from randomization to the date of disease progression or death from any cause

  3. Incidence of dose-limiting toxicities (DLTs) (Phase 2 only) [ Time Frame: During first cycle of treatment; up to one month ]
  4. Incidence of adverse events (AEs) (Phase 2 only) [ Time Frame: 18 months ]
  5. Incidence of dose modifications (Phase 2 only) [ Time Frame: 18 months ]

Secondary Outcome Measures :
  1. Confirmed objective response rate (ORR) per Response evaluation criteria in solid tumors (RECIST) version 1.1 according to investigator assessment (Phases 2 and 3) [ Time Frame: 36 months ]
    Confirmed ORR is defined as confirmed complete response (CR) or partial response (PR) in subjects with measurable disease.

  2. ORR RECIST version 1.1 according to investigator assessment (Phases 2 and 3) [ Time Frame: 36 months ]
  3. Duration of response (DOR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) [ Time Frame: 36 months ]
  4. Disease control rate (DCR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) [ Time Frame: 36 months ]
    DCR is defined as subjects with CR, PR, or stable disease (SD or non-CR/non-progressive disease)

  5. PFS per RECIST v1.1 according to blinded independent central review (BICR) assessment (Phase 3 only) [ Time Frame: 36 months ]
  6. Confirmed ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [ Time Frame: 36 months ]
  7. ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [ Time Frame: 36 months ]
  8. DOR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [ Time Frame: 36 months ]
  9. DCR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [ Time Frame: 36 months ]
  10. Incidence of AEs (Phase 3 only) [ Time Frame: 36 months ]
  11. Incidence of dose modifications (Phase 3 only) [ Time Frame: 36 months ]
  12. PFS per RECIST version 1.1 according to investigator assessment (Phase 2 only) [ Time Frame: 18 months ]
  13. Area under the plasma concentration-time curve (AUC) to the time of the last quantifiable concentration (AUClast) of tucatinib (Phase 2 only) [ Time Frame: 1 month ]
    Pharmacokinetic (PK) parameter

  14. AUC to AUClast of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter

  15. Maximum observed concentration (Cmax) of tucatinib (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter

  16. Cmax of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter

  17. Time of Cmax (Tmax) of tucatinib (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter

  18. Tmax of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter

  19. Trough concentration (Ctrough) of tucatinib (Phase 2 only) [ Time Frame: 18 months ]
    PK parameter

  20. Ctrough of tucatinib (Phase 2 only) [ Time Frame: 18 months ]
    PK parameter

  21. Metabolic ratio of tucatinib based on AUC (MRAUC) (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter

  22. MRAUC of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC)
  • HER2+ disease at screening, as follows:

    • Phase 2 paclitaxel dose optimization stage: HER2 amplification in a blood-based NGS assay performed at a central laboratory or centrally confirmed HER2 overexpression/amplification in a tumor biopsy obtained after progression of the most recent line of systemic therapy, evaluated following the package insert of FDA-approved tests for immunohistochemistry (IHC) and in situ hybridization (ISH) (IHC3+ or IHC2+/ISH+)
    • Phase 2 dose expansion stage:

      • Cohort 2A: HER2 amplification in a blood-based NGS assay performed at a central laboratory
      • Cohort 2B: centrally confirmed HER2 overexpression/amplification in a tumor biopsy obtained after progression of the most recent line of systemic therapy, evaluated following the package insert of FDA-approved tests for IHC and ISH (IHC3+ or IHC2+/ISH+)
    • Phase 3: HER2 amplification in a blood-based NGS assay performed at a central laboratory
  • History of prior treatment with a HER2-directed antibody
  • Progressive disease during or after first-line therapy for locally-advanced unresectable or metastatic GEC
  • Phase 2: Measurable disease according to RECIST version 1.1
  • Phase 3: Measurable or non-measurable disease according to RECIST version 1.1
  • Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
  • Life expectancy of at least 3 months, in the opinion of the investigator
  • Adequate baseline hematologic parameters and hepatic function

Exclusion Criteria:

  • Subjects with squamous cell or undifferentiated GEC
  • Having received more than 1 line of prior systemic therapy for locally-advanced unresectable or metastatic disease
  • Having received taxanes ≤12 months prior to enrollment, prior treatment with ramucirumab, or prior treatment with tucatinib, lapatinib, neratinib, afatinib, or any other investigational anti-HER2 and/or anti-EGFR tyrosine kinase inhibitor, or with T-DM1, DS8201a, or any other HER2-directed antibody-drug conjugate
  • History of exposure to the following cumulative doses of anthracyclines:

    • Doxorubicin >360 mg/m²
    • Epirubicin >720 mg/m²
    • Mitoxantrone >120 mg/m²
    • Idarubicin >90 mg/m²
    • Liposomal doxorubicin (e.g. Doxil, Caelyx, Myocet) >550 mg/m²
  • History of allergic reactions to paclitaxel, trastuzumab, ramucirumab, or compounds chemically or biologically similar to tucatinib, except for Grade 1 or 2 infusion-related reactions to trastuzumab or ramucirumab that were successfully managed, or known allergy to any of the excipients in the study drugs or placebos
  • Phase 2 paclitaxel dose optimization stage only: history of prior partial or total gastrectomy
  • Treatment with any systemic anti-cancer therapy (including hormonal and biologic therapy), radiation, or an experimental agent, or participation in another interventional clinical trial ≤3 weeks prior to first dose of study treatment.
  • Major surgery within 28 days prior to enrollment or randomization, central venous access device placement within 7 days prior to enrollment or randomization, or planned major surgery following initiation of study treatment
  • Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:

    • Anemia
    • Alopecia
    • Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely
  • Clinically significant cardiopulmonary disease
  • Known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment
  • Known to be positive for hepatitis B by surface antigen expression. Known to be positive for hepatitis C infection (positive by polymerase chain reaction). Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks
  • Presence of known chronic liver disease
  • Phase 2: Known to be positive for human immunodeficiency virus (HIV)
  • Phase 3: Subjects known to be positive for HIV are excluded if they meet any of the following criteria:

    • CD4+ T-cell count of <350 cells/uL
    • Detectable HIV viral load
    • History of an opportunistic infection within the past 12 months
    • On stable antiretroviral therapy for <4 weeks
  • Subjects who are pregnant, breastfeeding, or planning to become pregnant from time of informed consent until 7 months following the last dose of study drug
  • Unable to swallow pills or requires enteral feeding
  • Have used a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong CYP2C8 or CYP3A4 inducer within 5 days prior to first dose of study treatment.
  • History of malignancy other than GEC within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year OS of ≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
  • History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism during the 3 months prior to enrollment or randomization.
  • Therapeutic anticoagulation with warfarin, low-molecular weight heparin or similar agents. Subjects receiving prophylactic, low-dose anticoagulation therapy are eligible provided that the coagulation parameters defined in the inclusion criteria (INR ≤1.5 and PTT/aPTT ≤1.5 ULN) or (PT ≤1.5 ULN and PTT/aPTT ≤1.5 ULN) are met.
  • Chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs, e.g., indomethacin, ibuprofen, naproxen, or similar agents) or other anti-platelet agents (e.g., clopidogrel, ticlopidine, dipyridamole, anagrelide). Aspirin use at doses up to 325 mg/day is permitted.
  • Significant bleeding disorders, vasculitis, or had a significant bleeding episode from the gastrointestinal tract within 3 months prior to study entry.
  • History of any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to enrollment or randomization.
  • History of gastrointestinal perforation and/or fistulae within 6 months prior to enrollment or randomization.
  • Serious non-healing wound or peptic ulcer or bone fracture within 28 days prior to enrollment or randomization
  • History of bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis or chronic diarrhea
  • Active or uncontrolled clinically serious infection
  • Known active central nervous system metastases. Irradiated or resected lesions are permitted, provided the lesions are fully treated and inactive, subject is asymptomatic, and no steroids have been administered for at least 30 days.
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Responsible Party: Seattle Genetics, Inc.
ClinicalTrials.gov Identifier: NCT04499924    
Other Study ID Numbers: SGNTUC-022
First Posted: August 5, 2020    Key Record Dates
Last Update Posted: August 5, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Seattle Genetics, Inc.:
HER2+
HER2-positive
GEA
GEC
GEJ
Additional relevant MeSH terms:
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Adenocarcinoma
Esophageal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Paclitaxel
Trastuzumab
Ramucirumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological