S1406 Irinotecan Hydrochloride and Cetuximab with or without Vemurafenib in Treating Patients with Colorectal Cancer That Is Metastatic or Locally Advanced and Cannot Be Removed by Surgery

Inclusion Criteria

• STEP I INITIAL REGISTRATION: BRAFV600E TESTING:
• Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is either metastatic, or locally advanced and unresectable; NOTE: in the event that both cecal and appendiceal primaries are considered, patient is eligible if it is concluded by the treating oncologist to most likely be cecal based on pathological, surgical, and clinical interpretation; clinical diagnosis must be clearly documented in the “Comments” section on the S1406 Onstudy Form
• Patients must have BRAFV600E mutant status documented by a Clinical Laboratory Improvements Amendments (CLIA) certified laboratory on a pathology report prior to Step 2 registration; use of an Food and Drug Administration (FDA)-approved test is preferred although other BRAF tests at a CLIA-certified laboratory will also be accepted * If a BRAFV600E mutation is known, then the patient must be registered to Step 2 Randomization immediately following Step 1 Initial Registration * If testing has not been performed locally, BRAFV600E testing must be completed by the central laboratory (lab) prior to Step 2 Randomization; if the specimen does not have a BRAFV600E mutation, the patient is ineligible for Step 2 Randomization
• Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 90 days prior to Step 1 Initial Registration; eligible patients should be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to Step 1 Initial Registration
• Patients must have had one or two prior regimens of systemic chemotherapy for metastatic or locally advanced, unresectable disease; (a maintenance regimen of 5-fluorouracil or capecitabine, with or without bevacizumab, should not be counted as a separate line of treatment); prior treatment with irinotecan is allowed; prior treatment for metastatic disease is not required for patients who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy
• Patients must not have been treated with any of the following prior to Step 1 Randomization: * Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR * BRAF inhibitor including, but not limited to, vemurafenib or dabrafenib; regorafenib is not considered a BRAF inhibitor for the purpose of determining trial eligibility * Mitogen-activated protein/extracellular signal–regulated kinase (MEK) inhibitor including, but not limited to, trametinib or selumetinib
• Known KRAS or NRAS mutations: * All patients must have molecular testing performed in a clinical lab which includes codon 12 and 13 of KRAS; patients with any mutation in codon 12 and 13 of KRAS are not eligible for the protocol * Testing for additional codons in KRAS or testing for NRAS is not required; however, if such testing has been performed in a clinical lab and any mutation in codons 61 or 146 in KRAS, or codons 12, 13, 61, or 146 in NRAS is detected, the patient is not eligible for the protocol
• SPECIMEN SUBMISSION CRITERIA:
• Patients must have tumor (slides or block) available for submission for V600E BRAF testing
• Patients must have additional tumor available and be willing to submit tissue and blood samples
• REGULATORY CRITERIA:
• Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; for Step 1 Initial Registration of patients who have not yet submitted specimens for the central BRAFV600E testing, the appropriate consent form is the Step 1 Consent Form; for both Step 1 Initial Registration and Step 2 Randomization of patients whose BRAF mutation status is already known, the appropriate consent form is the Step 2 Consent Form
• STEP 2 RANDOMIZATION:
• Patients with known BRAF mutation must be registered to Step 2 Randomization immediately following Step 1 Initial Registration; results of BRAF testing will be available on the Southwest Oncology Group (SWOG) specimen tracking website within 10 calendar days from submission of tissue specimen to Moffitt Cancer Center and patient must be registered to Step 2 within 60 days of Step 1 Initial Registration
• Patients must have BRAFV600E mutation
• Patients must have measurable or non-measurable diseases that is either metastatic or locally advanced and unresectable; computed tomography (CT) scans or magnetic resonance imagings (MRIs) used to assess all disease must have been completed within 28 days prior to Step 2 Randomization; CT scans or MRIs must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)
• Previous chemotherapy, immunotherapy, or radiation therapy must have been completed at least 14 days prior to Step 2 Randomization and all toxicity must be resolved to Common Toxicity Criteria for Adverse Events (CTCAE) version (v) 4.0 grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to Step 2 Randomization
• Patients must have a Zubrod performance status (PS) of 0-1
• Patients must have a complete physical examination and medical history within 28 days prior to Step 2 Randomization
• Absolute neutrophil count (ANC) >= 1,500/mcL (within 14 days prior to Step 2 Registration)
• Platelets >= 100,000/mcL (within 14 days prior to Step 2 Registration)
• Hemoglobin >= 9 g/dL (within 14 days prior to Step 2 Registration)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional upper limit of normal (IULN) or =< 5 x IULN if liver metastases are present (within 14 days prior to Step 2 Registration)
• Total bilirubin =< 1.5 x IULN (within 14 days prior to Step 2 Registration)
• Serum creatinine =< 1.5 x IULN within 14 days prior to Step 2 Randomization OR
• Calculated creatinine clearance > 60 ml/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to Step 2 Randomization
• Patients must have an electrocardiogram (ECG) within 14 days prior to Step 2 Randomization
• Patients must have corrected QT (QTc) =< 500 msec
• Patients must not have a known history of Gilbert’s syndrome or known homozygosity for the UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)*28 allele
• Patients must not have interstitial pneumonia or extensive symptomatic interstitial fibrosis of the lung
• Patients must not have an uncontrolled intercurrent illness including, but not limited to, active bleeding diathesis, uncontrolled infection/disorders, nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy, or psychiatric illness/social situations which would limit compliance with study requirements
• Patients must be able to swallow pill/tablet and have no refractory nausea, vomiting, malabsorption, external biliary shunt, or significant small bowel resection that would preclude adequate absorption
• Patients must not be pregnant or nursing due to risk of fetal or nursing infant harm; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for at least 60 days after study treatment; a woman is considered to be of “reproductive potential” if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, “effective contraception” also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years
• STEP 2 RANDOMIZATION REGULATORY CRITERIA:
• Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; for all patients, the appropriate consent form for this registration is the Step 2 Consent Form
• As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
• Patients (at institutions listed) must be offered the opportunity to participate in the optional S1406 Co-Clinical PDX Model trial; participating patients must have a fresh tissue biopsy for the Co-Clinical PDX Model Trial completed within 7 days of Step 2 Randomization
• STEP 3 CROSSOVER REGISTRATION:
• Patients must have documented disease progression while on Arm 1 of this protocol; the follow-up tumor assessment form documenting disease progression must be submitted to SWOG prior to Step 3 Crossover Registration
• Registration to Step 3 Crossover must be within 28 days of discontinuation of Arm 1 protocol treatment; patients going off treatment for any other reason are not eligible
• Patients must have a Zubrod performance status of 0-1
• ANC >= 1,500/mcL (within 14 days prior to Step 3 registration)
• Platelets >= 100,000/mcL (within 14 days prior to Step 3 registration)
• Hemoglobin >= 9 g/dL (within 14 days prior to Step 3 registration)
• AST and ALT =< 2.5 x IULN or =< 5 x IULN if liver metastases are present (within 14 days prior to Step 3 registration)
• Total bilirubin =< 1.5 x IULN (within 14 days prior to Step 3 registration)
• Serum creatinine =< 1.5 x IULN within 14 days prior to Step 3 registration OR
• Calculated creatinine clearance > 60 ml/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to Step 3 registration

PRIMARY OBJECTIVES:

I. To evaluate the progression-free survival (PFS) of v-raf murine sarcoma viral oncogene homolog B (BRAF) mutant metastatic colorectal cancer patients treated with irinotecan hydrochloride (irinotecan), cetuximab, and vemurafenib, compared to a control arm of irinotecan and cetuximab.

SECONDARY OBJECTIVES:

I. To evaluate the frequency and severity of toxicity associated with each of the treatment arms in this patient population.

OTHER OBJECTIVES:

I. To evaluate overall survival (OS) in treatment Arms 1 and 2.

II. To evaluate the overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, in treatment Arms 1 and 2 in the subset of patients with measurable disease.

III. To estimate rates of OS, ORR, and PFS in patients who register to Arm 3 after disease progression on Arm 1.

TRANSLATIONAL OBJECTIVES:

I. To evaluate genetic alterations, including low-frequency KRAS or NRAS mutations as detected by high-depth sequencing as predictive biomarkers of efficacy.

II. To evaluate PIK3CA pathway activation through PIK3CA mutations or PTEN protein loss as a predictive biomarker of innate resistance to this regimen.

III. To evaluate gene expression signatures from screened patients with v-raf murine sarcoma viral oncogene homolog B wild type (BRAFWT) and BRAFV600E tumors.

IV. To provide validation of BRAF immunohistochemistry (IHC) using complementary sequencing methodology from screened patients with BRAFWT and BRAFV600E tumors.

V. To confirm the estimated sensitivity of detectable BRAF V600E circulating cell-free deoxyribonucleic acid (DNA) as a non-invasive biomarker for BRAF V600E mutation as detected by IHC in the primary tumor.

VI. To correlate radiographic tumor response with change in quantification of BRAFV600E alleles in circulating cell-free DNA.

VII. To monitor for known mechanism of acquired resistance to epidermal growth factor receptor (EGFR) inhibition in circulating cell-free DNA.

VIII. To assess the correlation of treatment efficacy between the patients and the matched patient-derived xenograft (PDX) models.

IX. To assess the correlation between PDX mechanisms for resistance and circulating free DNA (cfDNA) in plasma samples of matched patients following progression of disease.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cetuximab intravenously (IV) over 60-120 minutes and irinotecan hydrochloride IV over 90 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross over to Arm II.

ARM II: Patients receive cetuximab and irinotecan hydrochloride as in Arm I and vemurafenib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 3 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
SWOG

Principal Investigator
Edmund Scott Kopetz

• Primary ID S1406
• Secondary IDs NCI-2014-00814
• Clinicaltrials.gov ID NCT02164916