Clinical Trials /

Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer

NCT04499924

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: SGNTUC-022
  • NCT ID: NCT04499924

Conditions

  • Gastric Adenocarcinoma
  • Gastroesophageal Junction Adenocarcinoma
  • Esophageal Adenocarcinoma

Interventions

DrugSynonymsArms
tucatinibTUKYSA, ONT-380, ARRY-380Arm 3A
trastuzumabArm 3A
ramucirumabCYRAMZAArm 3A
paclitaxelArm 3A

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Phase 2 ArmExperimentalTucatinib + trastuzumab + ramucirumab + paclitaxel
  • tucatinib
  • trastuzumab
  • ramucirumab
  • paclitaxel
Arm 3AExperimentalTucatinib + trastuzumab + ramucirumab + paclitaxel
  • tucatinib
  • trastuzumab
  • ramucirumab
  • paclitaxel
Arm 3BActive ComparatorRamucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo
  • ramucirumab
  • paclitaxel
Arm 3CExperimentalTucatinib + ramucirumab + paclitaxel + trastuzumab placebo
  • tucatinib
  • ramucirumab
  • paclitaxel

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS) (Phase 3 only)
Time Frame:60 months
Safety Issue:
Description:OS is defined as the time from randomization to death due to any cause

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:Confirmed ORR is defined as confirmed complete response (CR) or partial response (PR) in subjects with measurable disease.
Measure:ORR RECIST version 1.1 according to investigator assessment (Phases 2 and 3)
Time Frame:36 months
Safety Issue:
Description:
Measure:Duration of response (DOR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3)
Time Frame:36 months
Safety Issue:
Description:
Measure:Disease control rate (DCR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3)
Time Frame:36 months
Safety Issue:
Description:DCR is defined as subjects with CR, PR, or stable disease (SD or non-CR/non-progressive disease)
Measure:PFS per RECIST v1.1 according to blinded independent central review (BICR) assessment (Phase 3 only)
Time Frame:36 months
Safety Issue:
Description:
Measure:Confirmed ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only)
Time Frame:36 months
Safety Issue:
Description:
Measure:ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only)
Time Frame:36 months
Safety Issue:
Description:
Measure:DOR per RECIST version 1.1 according to BICR assessment (Phase 3 only)
Time Frame:36 months
Safety Issue:
Description:
Measure:DCR per RECIST version 1.1 according to BICR assessment (Phase 3 only)
Time Frame:36 months
Safety Issue:
Description:
Measure:Incidence of AEs (Phase 3 only)
Time Frame:36 months
Safety Issue:
Description:
Measure:Incidence of dose modifications (Phase 3 only)
Time Frame:36 months
Safety Issue:
Description:
Measure:PFS per RECIST version 1.1 according to investigator assessment (Phase 2 only)
Time Frame:18 months
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:Pharmacokinetic (PK) parameter
Measure:AUC to AUClast of paclitaxel (Phase 2 only)
Time Frame:1 month
Safety Issue:
Description:PK parameter
Measure:Maximum observed concentration (Cmax) of tucatinib (Phase 2 only)
Time Frame:1 month
Safety Issue:
Description:PK parameter
Measure:Cmax of paclitaxel (Phase 2 only)
Time Frame:1 month
Safety Issue:
Description:PK parameter
Measure:Time of Cmax (Tmax) of tucatinib (Phase 2 only)
Time Frame:1 month
Safety Issue:
Description:PK parameter
Measure:Tmax of paclitaxel (Phase 2 only)
Time Frame:1 month
Safety Issue:
Description:PK parameter
Measure:Trough concentration (Ctrough) of tucatinib (Phase 2 only)
Time Frame:18 months
Safety Issue:
Description:PK parameter
Measure:Ctrough of tucatinib (Phase 2 only)
Time Frame:18 months
Safety Issue:
Description:PK parameter
Measure:Metabolic ratio of tucatinib based on AUC (MRAUC) (Phase 2 only)
Time Frame:1 month
Safety Issue:
Description:PK parameter
Measure:MRAUC of paclitaxel (Phase 2 only)
Time Frame:1 month
Safety Issue:
Description:PK parameter

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Seagen Inc.

Trial Keywords

  • HER2+
  • HER2-positive
  • GEA
  • GEC
  • GEJ
  • Seattle Genetics

Last Updated

April 13, 2021