Phase I/IB Multi-center Study of Irreversible EGFR/HER2 Tyrosine Kinase Inhibitor Afatinib (BIBW 2992) in Combination With Capecitabine for Advanced Solid Tumors and Pancretico-Biliary Cancers
Overview
- Phase
- Phase 1
- Intervention
- Afatinib Dimaleate
- Conditions
- Advanced Malignant Solid Neoplasm
- Sponsor
- University of Washington
- Enrollment
- 41
- Locations
- 2
- Primary Endpoint
- Incidence of adverse events, assessed according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This phase I/Ib trial studies the side effects and best dose of afatinib dimaleate when given together with capecitabine in treating patients with solid tumors, pancreatic cancer, or biliary cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment and has not responded to previous treatment. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving afatinib dimaleate together with capecitabine may be a better treatment for solid tumors, pancreatic cancer, or biliary cancer.
Detailed Description
PRIMARY OBJECTIVES: I. Evaluate the safety, maximum tolerated dose (MTD), and the recommended phase II dose (RP2D) of afatinib dimaleate (afatinib) in combination with capecitabine in patients with advanced solid tumors (phase I) and pancreatico-biliary cancers (phase Ib). (Phase I/Ib) SECONDARY OBJECTIVES: I. Evaluate biomarkers of response from tumor biopsies, including markers related to the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) pathways via OncoPlex or other equivalent gene sequencing assay. (Phase I/Ib) II. Evaluate rates of response and stable disease, duration of response, time to progression, progression-free and overall survival. (Phase I/Ib) OUTLINE: This is a phase I, dose-escalation study of afatinib dimaleate followed by a phase Ib study. Patients receive afatinib dimaleate orally (PO) once daily (QD) on days 1-21 and capecitabine PO twice daily (BID) on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 3 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •PHASE I: Histologically confirmed solid tumor malignancy
- •PHASE I: Life expectancy \>= 12 weeks
- •PHASE I: No limit on the number of prior systemic therapies for metastatic disease
- •PHASE I: Prior treatment with erlotinib, gefitinib or EGFR-blocking monoclonal antibodies (cetuximab and panitumumab) is allowed
- •PHASE I: Signed informed consent
- •PHASE I: Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2
- •PHASE I: Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
- •PHASE I: Must be willing to provide tumor tissue biopsy samples (may be fresh or archival paraffin embedded) at baseline
- •PHASE I: In order to perform a retrospective biomarker analysis with the next generation gene sequencing UW-OncoPlex assay; fresh tumor biopsies from metastatic or primary tumor lesion will be done if considered safe and feasible by treating physician and radiologist; Patients who already have OncoPlex or other equivalent gene sequencing assay (eg Foundation One, Perthera, Caris etc) test results available from prior tumor biopsy are eligible to participate, without the needed of a repeat tumor biopsy, but the test results need to be provided to the study principal investigator
- •PHASE I: Females of childbearing potential must use an effective method of contraception (barrier method of birth control or abstinence) from the time of consent until at least 180 days following discontinuation of protocol therapy; females of childbearing potential must have a negative pregnancy test within 3 days prior to registration for protocol therapy; patients are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months; females must not be pregnant or breastfeeding; in rare cases of an endocrine-secreting tumor, human chorionic gonadotropin (hCG) levels may be above normal limits (falsely-positive) but with no pregnancy in the patient; in these cases, there should be a repeat serum hCG test (with a non-rising result) to rule out pregnancy; upon confirmation of results and discussion with the Sponsor-Investigator, these patients may enter the study
Exclusion Criteria
- •Prior treatment with afatinib
- •Untreated or symptomatic brain metastases requiring corticosteroid therapy (no corticosteroid use for this purpose in the preceding 4 weeks)
- •Diagnosis with any of the following in the 12 months prior to registration: severe/unstable angina, myocardial infarction, uncontrolled cardiac arrhythmia, congestive heart failure, cerebrovascular accident or transient ischemic attack
- •Active venous thrombosis with contraindication for anticoagulation
- •Patients taking warfarin; if anticoagulation is required, the patient must be on a stable dose of a Food and Drug Administration (FDA) approved anticoagulant other than warfarin (e.g. enoxaparin, dalteparin, fondaparinux, apixaban, rivaroxaban) for at least 30 days
- •Any history of or concomitant condition that, in the opinion of the investigator, would compromise the patient?s ability to comply with the study or interfere with the evaluation of the efficacy and safety of the test drug
- •Gastrointestinal tract disease or any other reasons resulting in an inability to take oral medication or a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, active peptic ulcer disease or chronic diarrhea
- •History of bone marrow transplant and stem cell rescue
- •Receipt of any chemotherapy, biological therapy or investigational agents within 3 weeks prior to study registration
- •Radiotherapy within 4 weeks prior to therapy except palliative radiation to target organs other than primary tumor may be allowed up to 2 weeks prior to registration
Arms & Interventions
Treatment (afatinib dimaleate, capecitabine)
Patients receive afatinib dimaleate PO QD on days 1-21 and capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Afatinib Dimaleate
Treatment (afatinib dimaleate, capecitabine)
Patients receive afatinib dimaleate PO QD on days 1-21 and capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Capecitabine
Treatment (afatinib dimaleate, capecitabine)
Patients receive afatinib dimaleate PO QD on days 1-21 and capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Outcomes
Primary Outcomes
Incidence of adverse events, assessed according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame: Up to 30 days following the last dose of study treatment
Adverse events will be tabulated and summarized by dose levels. Summary tabulations will be presented displaying the number of observations, mean, standard deviation, median, minimum, and maximum for continuous variables, and the number and percentage per category for categorical data. Toxicity measurement will be accompanied by 90% confidence intervals.
Incidence of dose limiting toxicity (DLT) graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase Ib)
Time Frame: Up to 21 days
DLTs will be tabulated and summarized by dose levels. Summary tabulations will be presented displaying the number of observations, mean, standard deviation, median, minimum, and maximum for continuous variables, and the number and percentage per category for categorical data. Toxicity measurement will be accompanied by 90% confidence intervals.
Maximum tolerated dose (MTD) of afatinib dimaleate in combination with capecitabine (Phase Ib)
Time Frame: Up to 21 days
Defined as the dose at which 0/3 or =\< 1/6 patients experience a DLT graded according to NCI CTCAE version 4.0, will be assessed.
Recommended phase 2 dose (RP2D) (Phase Ib)
Time Frame: Up to 3 years
Defined as the best tolerated dose overall, considering overall toxicity, including beyond course 1, will be evaluated.
Secondary Outcomes
- Biomarker profile (including EGFR and HER2 gene copy number and mutations, Kirsten rat sarcoma viral oncogene homolog, B-Raf proto-oncogene, serine/threonine kinase, neuroblastoma RAS viral oncogene homolog NRAS mutations, and E-cadherin expression)(Baseline)
- Duration of response(Time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the first date that recurrent or progressive disease is objectively documented, assessed up to 3 years)
- Duration of stable disease(Time that stable disease is documented until the first date that recurrent disease is objectively documented, assessed up to 3 years)
- Overall survival(From the day of first treatment to the earlier of (1) death (from any cause) and (2) the last date of subject contact, assessed up to 3 years)
- Progression-free survival(From time from registration to disease progression or death of any cause, assessed up to 3 years)
- Rates of response, assessed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria(Up to 3 years)
- Stable disease, defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to quality for progressive disease assessed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria(Up to 3 years)
- Time to progression(From the study enrollment until the criteria for disease progression are met (or death occurs), assessed up to 3 years)