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A Study of Tucatinib (ONT-380) Combined With Capecitabine and/or Trastuzumab in Patients With HER2+ Metastatic Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02025192
Recruitment Status : Active, not recruiting
First Posted : December 31, 2013
Last Update Posted : February 11, 2020
Sponsor:
Information provided by (Responsible Party):
Seattle Genetics, Inc.

Tracking Information
First Submitted Date  ICMJE December 17, 2013
First Posted Date  ICMJE December 31, 2013
Last Update Posted Date February 11, 2020
Actual Study Start Date  ICMJE December 31, 2013
Actual Primary Completion Date October 3, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 28, 2019)
  • Incidence of adverse events [ Time Frame: Up to approximately 4 years ]
  • Severity of adverse events [ Time Frame: Up to approximately 4 years ]
Original Primary Outcome Measures  ICMJE
 (submitted: December 27, 2013)
  • Incidence of adverse events [ Time Frame: 26 months ]
  • Severity of adverse events [ Time Frame: 26 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2019)
  • Incidence of clinical lab abnormalities (hematology, chemistry, liver function tests, coagulation, urinalysis) [ Time Frame: Up to approximately 4 years ]
  • Severity of clinical lab abnormalities (hematology, chemistry, liver function tests, coagulation, urinalysis) [ Time Frame: Up to approximately 4 years ]
  • Frequency of dose reductions in tucatinib (ONT-380 [ Time Frame: Up to approximately 4 years ]
  • Frequency of dose reductions in capecitabine [ Time Frame: Up to approximately 4 years ]
  • Plasma concentrations of tucatinib (ONT-380) and metabolite [ Time Frame: 26 months ]
  • Plasma concentrations of capecitabine and metabolites [ Time Frame: 26 months ]
  • Objective response rate (ORR) [ Time Frame: 26 months ]
    Objective response (OR) will be defined as a best response of complete response (CR) or partial response (PR). The ORR will be calculated as the proportion of patients in the Efficacy Evaluable Patient Set who achieve an objective response.
  • Duration of response [ Time Frame: 26 months ]
  • Disease control rate [ Time Frame: 26 months ]
    Disease control will be defined as a best response of CR, PR, or stable disease (SD). The DCR will be calculated as the proportion of patients in the Efficacy Evaluable Patient Set who achieve disease control.
  • Clinical benefit rate (CBR) [ Time Frame: 26 months ]
    Clinical benefit will be defined as a best response of CR, PR, or SD for ≥ 6 months. The CBR will be calculated as the proportion of patients in the Efficacy Evaluable Patient Set who achieve clinical benefit.
  • Progression-free survival (PFS) [ Time Frame: Up to 6 years ]
    PFS will be defined as the time from first dose of study drug until documentation of disease progression or death from any cause
Original Secondary Outcome Measures  ICMJE
 (submitted: December 27, 2013)
  • Incidence of clinical lab abnormalities (hematology, chemistry, liver function tests, coagulation, urinalysis) [ Time Frame: 26 months ]
  • Severity of clinical lab abnormalities (hematology, chemistry, liver function tests, coagulation, urinalysis) [ Time Frame: 26 months ]
  • Frequency of dose reductions in ONT-380 (%) [ Time Frame: 26 months ]
  • Frequency of dose reductions in capecitabine (%) [ Time Frame: 26 months ]
  • Plasma concentrations of ONT-380 and metabolite [ Time Frame: 26 months ]
  • Plasma concentrations of capecitabine and metabolites [ Time Frame: 26 months ]
  • Objective response rate (ORR) (%) [ Time Frame: 26 months ]
  • Duration of response (days) [ Time Frame: 26 months ]
  • Disease control rate (best response of CR, PR, or SD) (%) [ Time Frame: 26 months ]
  • Clinical benefit rate (CBR) (SD for ≥ 6 months, PR, or SR) (%) [ Time Frame: 26 months ]
  • Progression-free survival (PFS) (days) [ Time Frame: 26 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Tucatinib (ONT-380) Combined With Capecitabine and/or Trastuzumab in Patients With HER2+ Metastatic Breast Cancer
Official Title  ICMJE A Phase 1b, Open-label Study to Assess the Safety and Tolerability of Tucatinib (ONT-380) Combined With Capecitabine and Trastuzumab, Alone and in Combination in HER2+ Metastatic Breast Cancer
Brief Summary The purpose of this study is to determine the maximal tolerated dose (MTD) or recommended phase 2 dose (RP2D) of tucatinib (ONT-380) and to assess the safety and tolerability of tucatinib (ONT-380) combined with capecitabine alone, trastuzumab alone and with both capecitabine and trastuzumab in patients with HER2+ metastatic breast cancer.
Detailed Description

This is a study of tucatinib (ONT-380) given in combination with capecitabine alone, trastuzumab alone and with both capecitabine and trastuzumab in patients with HER2+ metastatic breast cancer.

This study will use a 3+3 dose escalation design to evaluate escalating dose levels of tucatinib (ONT-380) in each of these three combinations in order to identify the maximal tolerated dose/recommended phase 2 dose (MTD/RP2D) of tucatinib (ONT-380). The MTD/RP2D of tucatinib (ONT-380) to be used in combination with either capecitabine alone (Combination 1) or trastuzumab alone (Combination 2) will be determined prior to evaluating tucatinib (ONT-380) in combination with both capecitabine and trastuzumab (Combination 3). If Combination 1 and Combination 2 are found to be tolerable, then tucatinib (ONT-380) will be evaluated in Combination 3, using the lowest MTD/RP2D or other SMC-recommended dose of tucatinib (ONT-380) determined for either of the two drug combinations. This will be followed by enrollment of an expansion cohort of patients treated at the MTD/RP2D for Combination 3. Additional expansion cohorts for either Combination 1 (tucatinib (ONT-380) and capecitabine) or Combination 2 (tucatinib (ONT-380) and trastuzumab) may also be enrolled.

Capecitabine will be given twice per day orally at 1000 mg/m^2 on Days 1-14 of each 21-day cycle. Trastuzumab will be given as a loading dose of 8 mg/kg IV followed by 6 mg/kg once every 21 days. However, a loading dose of trastuzumab will not be given to patients who have received trastuzumab within 4 weeks of the first study dose of trastuzumab. These patients will receive trastuzumab at 6 mg/kg each cycle, including Cycle 1. Trastuzumab may also be given on a weekly basis at 2 mg/kg IV q 7 days, but only in the circumstance that trastuzumab infusion has been delayed, and weekly infusions are required to resynchronize the cycle length to 21 days, after discussion with the medical monitor. Trastuzumab infusion rates will be per institutional guidelines. Tucatinib (ONT-380) will be given twice per day orally at a dose dependent upon the dosing cohorts to which the patient is enrolled.

There will be 3-6 evaluable patients enrolled in each cohort in the dose escalation phase, unless that dose is found to be intolerable prior to completion of enrollment. At least 6 evaluable patients are to be treated at a dose level in order for an MTD/RP2D to be determined.

Provided that only seven dose cohorts are needed for dose escalation and only the expansion cohort for Combination 3 is enrolled, up to 66 evaluable patients may be enrolled. Additional patients may be enrolled if additional expansion cohorts are opened.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE HER2 Positive Metastatic Breast Cancers
Intervention  ICMJE
  • Drug: Tucatinib
    Administered twice per day, orally.
    Other Name: ONT-380
  • Drug: Capecitabine
    1000mg/m^2 administered twice per day, orally in Days 1-14 of each 21-day cycle.
    Other Name: Xeloda
  • Drug: Trastuzumab
    Administered at a loading dose of 8 mg/kg IV followed by 6 mg/kg once every 21 days.
    Other Name: Herceptin
Study Arms  ICMJE
  • Experimental: Tucatinib (ONT-380) in combination with capecitabine
    Interventions:
    • Drug: Tucatinib
    • Drug: Capecitabine
  • Experimental: Tucatinib (ONT-380) in combination with trastuzumab
    Interventions:
    • Drug: Tucatinib
    • Drug: Trastuzumab
  • Experimental: Tucatinib (ONT-380) combined with capecitabine and trastuzumab
    Interventions:
    • Drug: Tucatinib
    • Drug: Capecitabine
    • Drug: Trastuzumab
Publications * Murthy R, Borges VF, Conlin A, Chaves J, Chamberlain M, Gray T, Vo A, Hamilton E. Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018 Jul;19(7):880-888. doi: 10.1016/S1470-2045(18)30256-0. Epub 2018 May 24.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: January 25, 2016)
60
Original Estimated Enrollment  ICMJE
 (submitted: December 27, 2013)
138
Estimated Study Completion Date  ICMJE March 31, 2020
Actual Primary Completion Date October 3, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  • Metastatic breast cancer, documented as HER2+ by fluorescence in situ hybridization (FISH) and/or 3+ staining by immunohistochemistry (IHC).
  • Progressive disease, with a history of prior treatment with both trastuzumab and T-DM1 (unless deemed intolerant to or ineligible for T-DM1 by the investigator) for metastatic disease.
  • If female and of child-bearing potential, has negative pregnancy test within 14 days prior to treatment.
  • If a sexually active male or a sexually active female of child-bearing potential, agrees to use dual (two concurrent) forms of medically accepted contraception from the time of consent until 6 months after the last dose of ONT-380, capecitabine, or trastuzumab, whichever is longest.
  • Must have target or non-target lesions as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.
  • All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1, with the following exceptions: alopecia; neuropathy, which must have resolved to ≤ Grade 2; and congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence and must have resolved completely.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening.
  • In the opinion of the Investigator, life expectancy > 6 months.
  • Adequate hematologic function as defined by:

    1. Hemoglobin ≥ 9 g/dL
    2. Absolute neutrophil count (ANC) ≥ 1000 cells/μL
    3. Platelets ≥ 100,000/μL
  • Adequate hepatic function as defined by the following:

    1. Total bilirubin ≤ 1.5 X upper limit of normal (ULN), unless a known history of Gilbert's disease
    2. Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase [AST/SGOT] and alanine aminotransferase/serum glutamic pyruvic transaminase [ALT/SGPT]) ≤ 2.5 X ULN (< 5 X ULN if liver metastases are present)
  • International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN unless on medication known to alter INR and aPTT.
  • Creatinine clearance ≥ 50 mL/min.
  • Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study drug.

Exclusion Criteria

  • Medical, social, or psychosocial factors that, in the opinion of the Investigator, could impact safety or compliance with study procedures.
  • Patient is breastfeeding.
  • Previous treatment with any experimental agent within 14 days or five half-lives of study treatment, whichever is greater.
  • Previous treatment with trastuzumab or other antibody-based therapy within three weeks of starting study treatment or with chemotherapy or hormonal cancer therapy within two weeks of starting study treatment.
  • Previous treatment with cumulative dose of doxorubicin > 360 mg/m2 or previous treatment with another anthracycline with cumulative dose equivalent to > 360 mg/m2 doxorubicin.
  • Previous treatment with:

    1. Capecitabine for metastatic disease at any time, for patients assigned to cohorts using capecitabine plus ONT-380 (Combination 1) or capecitabine plus trastuzumab plus ONT-380 (Combination 3). However, patients who have previous treatment with capecitabine for metastatic disease are eligible for enrollment into cohorts using trastuzumab plus ONT-380 (Combination 2). Patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible to enroll into all cohorts (Combination 1, 2, or 3).
    2. Any small molecule HER2 inhibitors including (but not limited to) lapatinib, neratinib, or afatinib within the last 4 weeks prior to initiation of study therapy.
  • CNS disease:

    1. Patients with leptomeningeal disease are excluded.
    2. Dose escalation and expansion cohorts: Patients with symptomatic CNS metastases are excluded. Patients with treated CNS metastases or untreated asymptomatic CNS metastases not requiring immediate local therapy may be eligible. Enrollment of patients with metastases must be approved by the study medical monitor.
    3. Optional CNS disease expansion cohorts: Patients with untreated asymptomatic CNS metastases not requiring immediate local therapy or patients with progressive CNS disease following local therapy may be eligible with medical monitor approval.
  • History of allergic reactions to compounds of similar chemical or biological composition to capecitabine (for patients assigned to Combination 1 or 3 only), trastuzumab (for patients assigned to Combination 2 or 3 only), or ONT-380, except for a history of Grade 1 or Grade 2 Infusion Related Reaction to trastuzumab, which has been successfully managed.
  • Patients with uncorrectable electrolyte abnormalities.
  • Known to be HIV positive. HIV testing is not required for those patients who are not known to be positive.
  • Known carrier of Hepatitis B and / or Hepatitis C (whether active disease or not).
  • Known liver disease, autoimmune hepatitis, or sclerosing cholangitis.
  • Inability to swallow pills or any significant gastrointestinal diseases, which would preclude adequate absorption of oral medications.
  • Use of a strong CYP3A4 inhibitor or inducer within three elimination half-lives of the inhibitor or inducer prior to the start of study treatment.
  • Use of a strong CYP2C8 inducer or inhibitor within three elimination half-lives of the inducer or inhibitor prior to the start of study treatment. (See Appendix F).
  • Radiotherapy within 14 days of first dose of ONT-380; patient must have recovered from acute effects of radiotherapy to baseline.
  • Known impaired cardiac function or clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, congestive heart failure, and uncontrolled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg on antihypertensive medications).
  • Myocardial infarction or unstable angina within 6 months prior to the first dose of study drug.
  • Patient with known dihydropyrimidine dehydrogenase deficiency (for patients assigned to Combination 1 or 3 only).
  • Patient requiring warfarin therapy with known history of difficulty in management of maintaining INR within therapeutic range. Patients on warfarin may be included if on a stable dose with a therapeutic INR.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02025192
Other Study ID Numbers  ICMJE ONT-380-005
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Seattle Genetics, Inc.
Study Sponsor  ICMJE Seattle Genetics, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: JoAl Mayor, PharmD, BCOP Seattle Genetics, Inc.
Study Director: Corinna Palanca-Wessels, MD, PhD Seattle Genetics, Inc.
PRS Account Seattle Genetics, Inc.
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP