Afatinib Dimaleate and Capecitabine in Treating Patients With Advanced Refractory Solid Tumors, Pancreatic Cancer or Biliary Cancer



Status:Recruiting
Conditions:Cancer, Cancer, Cancer, Cancer, Cancer, Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:19 - Any
Updated:12/22/2018
Start Date:November 5, 2015

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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

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.

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.

Inclusion Criteria:

PHASE I:

- 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

- PHASE I: Sexually active male subjects 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

- PHASE I: Absolute neutrophil count >= 1500/uL

- PHASE I: Platelet count >= 100,000/uL

- PHASE I: Hemoglobin >= 9 gm/dL

- PHASE I: Total bilirubin =< 1.5 times upper limit of normal (ULN)

- PHASE I: Transaminases (aspartate aminotransferase [AST] and/or alanine
aminotransferase [ALT]) =< 2.5 x ULN

- PHASE I: Prothrombin time (PT) (or international normalized ratio [INR]) and partial
thromboplastin time (PTT) =< 1.5 x ULN

- PHASE I: Calculated creatinine clearance (CrCl) >= 60 mL/min calculated by
Cockcroft-Gault formula

PHASE IB:

- PHASE IB: Histologically confirmed refractory locally-advanced unresectable or
metastatic pancreatic or biliary cancer

- PHASE IB: Life expectancy >= 12 weeks

- PHASE IB: =< 2 lines of prior systemic therapy for metastatic disease (if patients
have metastatic disease)

- PHASE IB: =< 2 lines of prior systemic therapy for patients with progressive
locally-advanced disease

- PHASE IB: No prior treatment with erlotinib is allowed for pancreatic cancer patients

- PHASE IB: ECOG PS 0-1

- PHASE IB: Signed informed consent

- PHASE IB: Measurable disease according to RECIST v1.1

- PHASE IB: Must be willing to provide tumor tissue biopsy samples (may be fresh or
archival paraffin embedded) at baseline

- PHASE IB: Fresh tumor biopsies from metastatic or primary tumor lesions will be done
only 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 available to the study principal investigator

- PHASE IB: 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, 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

- PHASE IB: Sexually active male subjects 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

- PHASE IB: Patients in the expansion cohort must have a measurable site of disease
according to RECIST (v 1.1) that has not been previously irradiated, or evidence of at
least 20% progression in a previously irradiated lesion, and assessed by imaging
within 28 days prior to registration for protocol therapy

- PHASE IB: Absolute neutrophil count >= 1500/uL

- PHASE IB: Platelet count >= 100,000/uL

- PHASE IB: Hemoglobin >= 9 gm/dL

- PHASE IB: Total bilirubin =< 1.5 times upper limit of normal (ULN)

- PHASE IB: Transaminases (AST and/or ALT) =< 2.5 x ULN

- PHASE IB: PT (or INR) and PTT =< 1.5 x ULN

- PHASE IB: Calculated creatinine clearance (CrCl) >= 60 mL/min calculated by
Cockcroft-Gault formula

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

- Major surgery within 4 weeks before starting study treatment or scheduled for surgery
during the projected course of the study

- Known pre-existing interstitial lung disease

- Any history or presence of poorly controlled gastrointestinal disorders that could
affect the absorption of the study drug (e.g. Crohn?s disease, ulcerative colitis,
chronic diarrhea, malabsorption)

- Known active hepatitis B infection (defined as presence of hepatitis B [HepB] surface
antigen [sAg] and/or Hep B deoxyribonucleic acid [DNA]), known active hepatitis C
infection (defined as presence of hepatitis C [Hep C] ribonucleic acid [RNA]) and/or
known human immunodeficiency virus (HIV) carrier
We found this trial at
2
sites
535 Barnhill Dr
Indianapolis, Indiana 46202
(888) 600-4822
Principal Investigator: Safi Shahda
Phone: 317-274-3512
Indiana University Melvin and Bren Simon Cancer Center At the IU Simon Cancer Center, more...
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Seattle, Washington 98109
Principal Investigator: Elena G. Chiorean
Phone: 206-288-6248
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Seattle, WA
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