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CTSU E1609 - "A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy versus High-Dose Interferon α-2b for Resected High-Risk Melanoma"
NOTE: Investigator training/exam on toxicity profile of Ipilimumab is MANDATORY b/f enrolling 1st pt. CTSU will block enrollments until this is completed.
Treatment Plan (Supplied Drug: Ipilimumab)
RANDOMIZATION
Arm A - Ipilimumab Highdose
Induction Phase
Ipilimumab: 10mg/kg, IV, q 3 wks x 4 doses
MAINTENANCE PHASE
Ipilimumab: 10mg/kg, IV, q 12 wks (starting Wk 24), x 4 doses max (Wks 24, 36, 48, 60)
Arm B - High-Dose Interferon α-2b (HDI)
Induction Phase
Interferon Alfa-2b: 20 MU/m2/d, IV, x 5 consecutive days out of 7 (M-F), weekly x 4 wks
MAINTENANCE PHASE
Interferon Alfa-2b: 10 MU/m2/d, SQ, QOD (M, W, F), 3x/wk x 48 wks
Arm C - Ipilimumab Lowdose
INDUCTION PHASE
Ipilimumab: 3mg/kg, IV, q 3 wks x 4 doses
MAINTENANCE PHASE
Ipilimumab: 3mg/kg, IV, q 12 wks (starting Wk 24), x 4 doses max (Wks 24, 36, 48, 60)
Eligibility
Age >18.
Disease must be completely surgically resected & be disease-free w/negative margins on resected specimen. No pts disease-free by non-surgical means. Disease-free documentation by PE & imaging w/i 4 wks pre-randomiz.
Prim cutaneous melanoma (Stg IIIB, IIIC, or IV) by 2009 AJCC Melanoma Staging System (see protocol). Stg IV pts must have LDH w/i IULN (<4 wks pre-randomiz) & either distant skin, subcutaneous, LN, or lung mets but no other visceral mets.
Pts w/disease recurrence after adequate surgical resection of orig primary cutaneous melanoma are allowed if:
Recurrence is in a regional LN basin after a complete LN dissection. Relapsed disease must be completely surgically resected w/free margins.
Recurrence is in-transit or satellite mets or distant skin/subcutaneous, nodal, or lung mets that are completely surgically resected w/free margins.
Recurrence is in a regional LN basin. Relapsed disease must be completely surgically resected w/free margins.
Pts w/unknown prim melanoma (Tx) who have cutaneous, subcutaneous, nodal, &/or lung mets that are completely surgically resected w/free margins are allowed, even if they don't fit strict staging criteria above. Stg IV pts must have LDH w/i IULN w/i 4 wks pre-randomiz (no M1c pts).
NOTE: All pts should be classified as IIIB, IIIC, M1a, or M1b including those w/disease recurrence after adequate surg excision of orig primary melanoma (see protocol for further instructions).
Randomiz w/i 84 days (12 wks) of surgical resection. If >1 surgical procedure is required for disease-free status, pt must be randomized w/i 12 wks of last surgery.
No adjuv chemo, biotherapy, or limb perfusion after resection(s) that make pt eligible for this study. Prior RT, including after surgical resection, is allowed if >21 days from RT to start of study therapy.
No prior anti-CTLA4 monoclonal antibodies, prior CTLA4 inhibitor or agonist, prior CD137 agonist, or prior Interferon-α. Other prior txs for melanoma (i.e., IL-2, anti-tumor vaccine, chemo) are allowed if given b/f resection(s) that make pt eligible for this study & are completed >4 wks pre-randomiz.
ECOG perf status 0-1.
No active infection requiring current tx w/parenteral antibiotics.
No other significant medical, surgical, or psychiatric conditions. No med requirements or tx precluding compliance, contraindicating the use of Ipilimumab or HDI, or obscuring the interpretation of AEs (i.e., frequent diarrhea) - all investigator's opinion.
No prior inflammatory bowel disease (includes ulcerative colitis & Crohn's disease) or diverticulitis (diverticulosis is allowed).
No autoimmune disorders/conditions of immunosuppression requiring current ongoing tx w/systemic corticosteroids or other systemic immunosuppressants) - includes oral & topical steroids. Occasional (not continuous) use of steroid inhalers & replacement doses of steroids for adrenal insufficiency are allowed. Pts who d/c these classes of meds >2 wks pre-randomiz are eligible if pt is unlikely to require resumption of these meds during the study (investigator's opinion).
No prior symptomatic autoimmune disease, motor neuropathy considered of autoimmune origin, or other CNS autoimmune disease. Autoimmune hypothyroid disease or Type I diabetes on replacement tx are allowed.
No infectious disease vaccination <4 wks pre-randomiz.
No prisoners or pts involuntarily incarcerated for tx of psychiatric or physical illness.
No other current malignancies. Exceptions: Other malignancies continuously disease-free 5 yrs pre-randomiz; in situ cancer, LCIS in situ, cervical cancer in situ, atypical melanocytic hyperplasia, or melanoma in situ.
No pregnant or lactating women. Blood or urine pregnancy test required (if applicable - see protocol details). Men/Women of reproductive potential must use adequate contraception throughout study & x 26 wks after last Ipilimumab or HDI dose.
Within 4 wks pre-randomiz: WBC >3000/uL; ANC >1500/uL; platelets >100,000/uL; Hgb >10g/dL; serum creat <1.8mg/dl; SGOT/SGPT <2.5x ULN; serum bili 2x ULN (if Gilbert's Syndrome, then <3.0mg/dL); negative tests for HIV, HBV, & HCV.
PRESTUDY REQUIREMENTS (<28 days of starting study drugs):
H&P, ECOG perf status, wt, VS
Concomitant meds
Hematology: Hgb, Hct, RBC, WBC, platelets (direct platelet count), total & differential CBCs
Chemistry: Albumin, amylase, lipase, urea or BUN, creat, SGPT, SGOT, LDH, serum alk phos, direct & total bili, glucose, total protein, Na, K, Cl, HCO3, Ca, K
Immunologic: C-reactive protein, ANA, TSI, ATGAB, ATPOAB, Anticardiolipin (TOTAL)#
UA (if clinically indicated)
Serum or urine pregnancy test (b-HCG) - minim sensitivity 25IU/L or equiv of HCG
HIV, HBV, HCV
ECG
Ophthalmologic exam (if clinically indicate)
Imaging studies (w/i 4 wks pre-randomiz)*
QOL evaluation
Path samples for diagnostic review (MANDATORY)**
Biologic samples for banking (w/pt's consent)***
* Total body PET-CT (w/ or w/o brain) & brain MRI or CT (if MRI is contraindicated). If PET-CT can't be done, CT of neck, chest, abdomen, & pelvis should be done. Use MRI if CT can't be done. Any other imaging should have no evidence of disease.
** Prim melanoma (known prim cutaneous melanoma) - 1 H&E of prim melanoma & 15 unstained slides from thickest portion of tumor for immunostains (don't deparaffinise slides) OR the corresponding block. For lymphadenectomy - 1 H&E section of tumor bearing LNs only OR 2 unstained slides OR 2 H&E slides of each positive LN. Resected in-transit or satellite mets, cutaneous mets, LN mets, or lung mets - 1 H&E section of metastatic lesion & 15-20 unstained slides from thickest part of tumor OR the corresponding block. Submit w/i 1 mo of randomiz to ECOG Path Coordinating Office; Chicago, IL.
*** Perip blood mononuclear cells - Ten full 10cc green-top heparin tubes. Serum - Three 10cc red-top tubes. PAXgene RNA tube - One tube. ACD - One 10cc yellow-top tube. Contact KCCOP for kits. Ship same day as collected via FedEx (Mon-Thurs only) using the airbill in the kit. Ship green tubes ambient. Refrigerate red, yellow, & PAXgene RNA tubes immediately & ship at 2-8oC. Ship to Immunologic Monitoring & Cellular Products Lab; Pittsburgh, PA.
# If investigator elects not to perform these labs, alternatively submit 10ml red-top tube of serum to the ECOG immune monitoring lab. Bank & ship together w/other biological samples at next scheduled shipment.
Signed informed consent.