Details

Details

Title Randomized Phase II Study of Irinotecan and Cetuximab with or without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer.

IRB S1406

CC 15-230

Hospital Fairview, Florida Weston, Hillcrest, Independence, Main Campus, Mansfield, North Coast Cancer, South Pointe, Strongsville, Wooster

Phase Phase 2

Disease Colorectal

Drug Cetuximab, Irinotecan , Vemurafenib

Description

Description

Primary Objective
  • To evaluate the progression-free survival (PFS) of BRAF mutant metastatic colorectal cancer patients treated with irinotecan, cetuximab, and vemurafenib, compared to a control arm of irinotecan and cetuximab.
Secondary Objectives
  • To evaluate the frequency and severity of toxicity associated with each of the treatment arms in this patient population.
Other Objectives
  • To evaluate overall survival (OS) in treatment Arms 1 and 2.
  • 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.
  • To estimate rates of OS, ORR, and PFS in patients who register to Arm 3 after disease progression on Arm 1.
Translational Objectives
  • To evaluate genetic alterations, including low-frequency KRAS or NRAS mutations (definitive list of genes to be finalized after completion of enrollment based on latest scientific knowledge) as detected by high-depth sequencing as predictive biomarkers of efficacy.
  • To evaluate PIK3CA pathway activation through PIK3CA mutations or PTEN protein loss as a predictive biomarker of innate resistance to this regimen.
  • To evaluate gene expression signatures from screened patients with BRAFWT and BRAFV600E tumors.
  • To provide validation of BRAF IHC using complementary sequencing methodology from screened patients with BRAFWT and BRAFV600E tumors.
  • To confirm the estimated sensitivity of detectable BRAF V600E circulating cellfree DNA as a non-invasive biomarker for BRAF V600E mutation as detected by IHC in the primary tumor.
  • To correlate radiographic tumor response with change in quantification of BRAF V600E alleles in circulating cell-free DNA.
  • To monitor for known mechanism of acquired resistance to EGFR inhibition in circulating cell-free DNA (KRAS, NRAS mutations).
Inclusion Criteria

Inclusion Criteria

Step 1 Initial Registration: BRAFV600E Testing

If patient has already had BRAF testing, he or she must satisfy these eligibility criteria before being considered for Step 2 Randomization.

Disease Related Criteria
  1. 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.
  2. Patients must have BRAFV600E mutant status documented by a CLIA certified laboratory on a pathology report prior to Step 2 registration. Use of an 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 lab (see Section 15.1) prior to Step 2 Randomization. If the specimen does not have a BRAFV600E mutation, the patient is ineligible for Step 2 Randomization.
  3. 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.
  4. 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.
  5. Patients must not have been treated with any of the following prior to Step 1 Initial Registration:
    • 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.
    • MEK inhibitor including, but not limited to, trametinib or selumetinib.
  6. 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
  1. Patients must have tumor (slides or block) available for submission for V600E BRAF testing as described in Section 15.1.
  2. Patients must have additional tumor available and be willing to submit tissue and blood samples as described in Section 15.2.
Regulatory Criteria
  1. 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 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.

Clinical/Laboratory Criteria
  1. Patients must have BRAFV600E mutation.
  2. Patients must have measurable or non-measurable disease that is either metastatic or locally advanced and unresectable, as defined in Section 10.1. CT scans or 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 (RECIST 1.1).
  3. 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 CTCAE v4.0 Grade 1 (with the exception of CTCAE v4.0 Grade 2 neuropathy) prior to Step 2 Randomization.
  4. Patients must have a Zubrod Performance Status of 0-1. (See Section 10.4)
  5. Patients must be ≥ 18 years of age.
  6. Patients must have a complete physical examination and medical history within 28 days prior to Step 2 Randomization.
  7. Patients must have adequate hematologic function as evidenced by all of the following within 14 days prior to Step 2 registration: ANC ≥ 1,500/mcL; platelets ≥ 100,000/mcL; and hemoglobin ≥ 9 g/dL.
  8. Patients must have adequate hepatic function as evidenced by all of the following within 14 days prior to Step 2 registration: AST and ALT ≤ 2.5 x Institutional Upper Limit of Normal (IULN) or ≤ 5 x IULN if liver metastases are present; and total bilirubin ≤ 1.5 x IULN.
  9. Patients must have adequate kidney function as evidenced by at least ONE of the following:
    • 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. Calculated creatinine clearance = (140 - age) x wt (kg) x [0.85 (if female)]/72 x creatinine (mg/dL)
  10. Patients must have an ECG within 14 days prior to Step 2 Randomization. Patients must have QTc ≤ 500 msec.
  11. Patients must not have a known history of Gilbert's Syndrome or known homozygosity for the UGT1A1∗28 allele.
  12. Patients must not have interstitial pneumonia or extensive symptomatic interstitial fibrosis of the lung.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
Regulatory Criteria
  1. 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.
  2. As a part of the OPEN registration process (see Section 13.4 for OPEN access instructions) 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.
Specimen Submission Criteria
  1. Patients (at institutions listed in Section 15.4 only) must be offered the opportunity to participate in the optional S1406 Co-Clinical PDX Model Trial (see Section 15.4). 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
  1. Patients must have documented disease progression as defined in Section 10.0 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.
  2. Patients must have a Zubrod Performance Status of 0-1. (See Section 10.4)
  3. Patients must have adequate hematologic function as evidenced by all of the following within 14 days prior to Step 3 registration: ANC ≥ 1,500/mcL; platelets ≥ 100,000/mcL; and hemoglobin ≥ 9 g/dL.
  4. Patients must have adequate hepatic function as evidenced by all of the following within 14 days prior to Step 3 registration: AST and ALT ≤ 2.5 x Institutional Upper Limit of Normal (IULN) or ≤ 5 x IULN if liver metastases are present; and total bilirubin ≤ 1.5 x IULN.
  5. Patients must have adequate kidney function as evidenced by at least ONE of the following:
    • 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. Calculated creatinine clearance = (140 - age) x wt (kg) x [0.85 (if female)]/72 x creatinine (mg/dL)
Exclusion Criteria

Exclusion Criteria

Exclusion Criteria Not Available