NCI Community Oncology Research Program - Kansas City (NCORP-KC)
NCI Community Oncology Research Program - Kansas City (NCORP-KC)




NCI Community Oncology Research Program - Protocol Summary

ECOG-ACRIN EA6134 - "A Randomized Phase III trial of Dabrafenib + Trametinib followed by Ipilimumab + Nivolumab at Progression vs. Ipilimumab + Nivolumab followed by Dabrafenib + Trametinib at Progression in Patients With Advanced BRAFV600 Mutant Melanoma"

The summary below serves as a brief review of the treatment plan and eligibility for the protocol.


This summary is not intended to be used in place of the full eligibility & treatment information in the protocol.
 

Please follow the "Full Protocol" link or contact NCORP-KC for complete protocol information.



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Skin Clinical Trial

CANCER TYPE: Melanoma
RESEARCH BASE: ECOG-ACRIN
NCT NUMBER: NCT02224781
HIPPA FORM: DOWNLOAD HIPPA FORM

Consent Form: VIEW CONSENT FORM

BRIEF DESCRIPTION

Melanoma, unresectable, stage III or IV, BRAFV600 mutation, Dabrafenib + Trametinib followed by Ipilimumab + Nivolumab at progression VS. Ipilimumab + Nivolumab followed by Dabrafenib + Trametinib at progression.  DCP-001 Eligible



NOTES


Mandatory Investigator Training Course:


ECOG-ACRIN has developed a training course to provide additional information to enrolling investigators on the toxicity profile of the ipilimumab and nivolumab combination. Each investigator is required to take the training course entitled: EA6134 Ipilimumab and Nivolumab Immune Related Adverse Events: Summary and Recommended Management, prior to their first patient enrollment by accessing the following URL:  http://coccg.mindflash.com/PublicCoursePage.aspx?c=1232832108

Treatment Plan

Arm A

Cycle = 42 days

Nivolumab 1 mg/kg IV infusion Day 1 and 22 of Cycles 1 and 2   AND

Ipilimumab 3 mg/kg IV infusion Day 1 and 22 of Cycles 1 and 2

Maintenance:  Nivolumab 3 mg/kg IV infusion Day 1, 15 and 29 of cycles 3-14 (max 84 weeks).

At progression crossover to arm C

Arm C

Dabrafenib 150 mg po twice daily days 1-42 of each 6 week cycle, continuous   AND

Trametinib 2 mg po daily days 1-42 of each 6 week cycle, continuous

Arm B

Dabrafenib 150 mg po twice daily days 1-42 of each 6 week cycle, until progression   AND

Trametinib 2 mg po daily days 1-42 of each 6 week cycle, until progression

At progression crossover to Arm D

Arm D

Nivolumab 1 mg/kg IV infusion Day 1 and 22 of Cycles 1 and 2

Ipilimumab 3 mg/kg IV infusion Day 1 and 22 of Cycles 1 and 2

Maintenance:  Nivolumab 3 mg/kg IV infusion Day 1,15 and 29 of cycles 3-14 (max 84 weeks)



ELIGIBILITY

Step 1 Eligibility

  • Age ≥ 18 years
  • ECOG Performance status: 0 or 1
  • Women must not be pregnant or breast-feeding
  • Women of child-bearing potential and sexually active males must agree to use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for the duration of their participation in the study, and for at least 4 weeks after treatment with dabrafenib or for 4 months after dabrafenib in combination with trametinib.
  • Patients must have unresectable stage III or stage IV disease.
  • Patients must have measurable disease as defined in Section 6.1. All sites of disease must be evaluated within 4 weeks prior to randomization.
  • Patients must have histological or cytological confirmation of melanoma that is metastatic or unresectable and clearly progressive.
  • NOTE: Any patient with BRAFV600 mutant melanoma (whether cutaneous, acral or mucosal primary) who meets the eligibility criteria is eligible for participation in this trial. Patients with uveal melanoma are not eligibile for this trial.
  • Patients must have BRAFV600 mutation, identified by an FDA-approved test at a CLIA-certified lab.
  • Patients may have had prior systemic therapy in the adjuvant setting; however this adjuvant treatment must not have included a CTLA4 or PD1 pathway blocking antibody or a BRAF/MEK inhibitor. Also, patients may not have had any prior systemic treatment for advanced (measurable metastatic) disease.
  • Patients must have discontinued chemotherapy, immunotherapy or other investigational agents used in the adjuvant setting ≥ 4 weeks prior to entering the study and recovered from adverse events due to those agents. Mitomycin and nitrosoureas must have been discontinued at least 6 weeks prior to entering the study. Patients must have discontinued radiation therapy ≥ 2 weeks prior to entering the study and recovered from any adverse events associated with treatment. Prior surgery must be ≥ 4 weeks from registration and patients must be fully recovered from post surgical complications.
  • Patients must not receive any other investigational agents while on study or within four weeks prior to registration.
  • Patients are ineligible if they have any currently active CNS metastases. Patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery (SRS)) that have been stable on head MRI or contrast CT scan for at least 4 weeks following treatment and within 4 weeks prior to randomization could be eligible. Patients must not have taken any steroids ≤ 14 days prior to randomization for the purpose of managing their brain metastases. Patients with only Whole Brain irradiation for treatment of CNS metastases are ineligible.
  • Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast. Patients with other malignancies are eligible if they have been continuously disease-free for > 3 years prior to the time of registration. Patients with a history of RAS mutation-positive tumors are not eligible regardless of interval from the current study. Note: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in assessing eligibility.
  • Patients must have the following values for initial laboratory tests obtained within 4 weeks prior to randomization (ULN: institutional upper limit of normal):
    • White Blood Count ≥ 3,000/uL
    • ANC ≥ 1,500/uL
    • Platelet Count ≥ 100,000/uL
    • Hemoglobin > 9 g/dL
    • Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) ≥ 40ml/min. (CrCl= Wt (kg) x (140-age)*/72 x Cr. level, *female x 0.85)
    • AST and ALT ≤ 3 x ULN (≤ 5 x ULN for patients with documented liver metastases)
    • Alkaline Phosphatase ≤ 2 x ULN (≤ 5x ULN for patients with known liver involvement and ≤ 7x ULN for patients with known bone involvement)
    • Total Bilirubin ≤ 1.5 x ULN except subjects with normal direct bilirubin or those with known Gilbert’s syndrome
    • Serum LDH < 10 X ULN (patients with LDH > 10 X ULN are felt to have aggressive disease and should be considered for BRAF inhibitor therapy off protocol)
  • Patients must not have any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), including but not limited to, ongoing or active infection requiring parenteral antibiotics on day 1, history of bleeding diathesis or need for concurrent anticoagulation (INR ≤ 1.5 and PTT within 1.1 x ULN), or psychiatric illness/social situations that would limit compliance with study requirements, interfere with subject’s safety, or obtaining informed consent. Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site. Exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR. Consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate. Prophylactic low dose warfarin may be given to maintain central catheter patency.
  • Patients must not have a history of or evidence of cardiovascular risks including any of the following:
    • QT interval corrected for heart rate using the Bazett’s formula QTcB ≥ 480 msec.at baseline.
    • History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to registration.
    • History prior to registration or evidence of current ≥ Class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system. (See Appendix IX)
    • LVEF ≤ lower limit of normal on cardiac echo or MUGA.
    • Intra-cardiac defibrillator.
    • History of abnormal cardiac valve morphology (≥ grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study.
    • History or evidence of current clinically significant uncontrolled cardiac arrhythmias; Clarification: Subjects with atrial fibrillation controlled for >30 days prior to dosing are eligible.
    • Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy
  • Individuals who are known to be HIV infected are ineligible (Note: HIV testing is not required for entry into the study).
  • Patients with evidence of active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection are not eligible. Patients with cleared HBV and HCV infection will be allowed.
  • Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease. Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjögren’s syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), should be evaluated for the presence of target organ involvement and potential need for systemic treatment. If no systemic immune suppression is deemed necessary they can be eligible.
  • The following medications or non-drug thrapies are also prohibited while on treatment in this study:
    • Other anti-cancer therapies
    • Other investigational drugs
    Patients taking any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible (see Appendix XI).
  • Patients must not have history of retinal vein occlusion (RVO).
  • Patients must not have evidence of interstitial lung disease or pneumonitis.
  • Patients must not have malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib.





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