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Consent Forms
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CALGB C10001 - "A Phase II Trial of Sequential Chemotherapy, Imatinib Mesylate (Gleevec, STI571), and Transplantation for Adults With Newly Diagnosed Ph+ Acute Lymphoblastic Leukemia"
QARC approval required for TBI)
Treatment Plan (Supplied Drug: Imatinib Mesylate)
Course I - Remission Induction
Must begin Course II w/i 2 wks of ANC >1000/µl and platelets >100,000/µl. CALGB pts should have perip blood & BM submitted for CALGB 8461 & 9665 (if also enrolled on a CALGB tx protocol for previously untreated ALL) and CALGB 9862 at time of enrollment on CALGB C10001. SWOG pts must have perip blood & BM submitted for SWOG 9007 at time of enrollment on CALGB C10001.
Course II
Imatinib Mesylate (Gleevec): 400mg, PO, BID, Days 1-28
BM asp & bx on Day II-29 to assess response. If marrow M0 or M1, pts may continue protocol therapy. Submit BM asp & bx for CALGB 9862 on Day II-29.
Course III - CNS Prophylaxis
Begin w/i 1 wk of BM exam on Day II-29.
NOTE: Recommended that IV Vincristine be administered prior to initiation of IV Methotrexate. IT Methotrexate should be administered later in day (any time during IV Methotrexate.
Lumbar Puncture: For CSF exam for leukemia required on Days 1, 8, & 15. Perform anytime during 3-hr IV Methotrexate on these days, but recommended to be done at end of 3-hr IV Methotrexate infusion.
IT Methotrexate: 15mg total, IT, once weekly, x 3 wks (Days 1, 8, & 15) + 50mg Hydrocortisone
Vincristine: 2mg total, IV, once weekly, x 3 wks (Days 1, 8, & 15)
IV Methotrexate: 1000mg/m2, IV over 3 hrs (in 1 liter D5W or NS), Days 1, 8, & 15. Prior to beginning IV-Mtx, pts should be pre-hydrated w/500-1000mL D5W or NS plus 100 mEq/L of sodium bicarb. Continue hydration & maintain urine pH>6. Strongly recommended that addit hydration (w/D5W or NS plus 100 mEq/L of sodium bicarb) be given on Days III-2, III-9, & III-16 when pt returns for IV Leucovorin.
PO Methotrexate: 25mg/m2, PO, q6hrs, x 4 doses (total), beginning 6 hrs after starting IV-Mtx (Days 1 & 2, 8 & 9, 15 & 16). Dose of PO-Mtx will be adjusted to maintain serum Mtx level between 1-2µM.
Serum Mtx Levels: Days 2, 4, 9, 11, 16, & 18
IV Leucovorin: 25mg/m2, IV push, 6 hrs after 4th (last) PO-Mtx dose (i.e., 30 hrs after starting IV-Mtx)
PO Leucovorin: 5mg/m2, PO, q6hrs, x 8 doses &/or serum Mtx level <0.05µM (begin 12hrs after IV-Lcv)
Cotrimoxazole DS: 1 tab, PO, BID, 3 days/wk (for PCP prophylaxis until chemo completion) or inhaled aerosolized pentamidine (300mg, 1x/mo) if allergic to sulfonamides. Do not give Cotrimoxazole on same day as Mtx, but can be given later in same wk.
Bone Marrow Asp & Bx/Perip Blood: BM asp/bx on Day III-29. Perip blood & BM specimens for CALGB 9862 (mandatory) on Day III-29.
Course IV
No upper limit for time to recovery from cytopenia. Course IV should ideally start on or shortly after Day III-29.
Imatinib Mesylate (Gleevec): 400mg, PO, BID, Days 1-28
BM asp & bx on Day IV-29 to assess response. If marrow M0 or M1, pts may continue protocol therapy. Submit BM asp & bx for CALGB 9862 on Day IV-29.
Course V (transplants must be done at CALGB- or SWOG-approved transplant center)
(A): Allogeneic Transplant for Pts w/HLA-Matched Sibling Donor
May begin >72 hrs & <10 days after last dose of Gleevec in Course IV. All pts will have BM exam & RT-PCR assay (submit samples through CALGB 9862) on Day 30 post-transplant following Course V.
Allopurinol: 300mg, QD, Days -8 through -2 (start day prior to RT)
Fractionated Total Body RT: Days -7 through -4 (1320cGy/11fx/120cGy each) over 4 days. 3fx/day will be given on Days -7 through -5 and 2fx/day on Day -4. Separate each fx by >4 hrs. Males will receive 400cGy boost to testes.
Donor: Will receive G-CSF at 16µg/kg/day, SQ, starting 2 days pre-planned apheresis. Starting Day 3 of mobilization, apheresis & cell collection will proceed daily until minimum of 5 x 106 CD34+ cells/kg (recipient wt) are collected or to total of 5 aphereses.
VP-16: 60mg/kg (corrected body wt), IV over 4 hrs, Day -3
Tacrolimus: 0.05mg/kg/day, CI, Days -1 through +3. Give 0.03mg/kg/day, CI, Days +4 through +14. Give 0.03mg/kg/day, CI, Days +14 through +56 or in divided doses q12hrs or PO formulation (when tolerated) at ratio of 1:4 (IV:PO) in 2 divided doses/day based on last IV dose.
PBSC Transplant: Day 0
Methotrexate: 10mg/m2, IV, Day +1, starting 24hrs after PSC infusion is complete. Give 5mg/m2, IV, Days +3 & +6.
G-CSF: 5µg/kg/day, SQ, beginning Day +4 until ANC >1500/µL x 2 consecutive days or >5000/µL x 1 day.
(B): Autologous Transplantation for Pts Without an HLA-Matched Sibling Donor
Begin >72 hrs & <10 days following last dose of Gleevec in Course IV. Must have BM exam and RT-PCR assay (CALGB 9862) on Day 30 post-transplant following Course V.
PBSC Mobilization & Leukapheresis
Etoposide: 10mg/kg/day (corrected body wt), CI over 96 hrs, Days 1-4. Total dose = 40mg/kg.
Ara-C: 2000mg/m2, IV over 2 hrs, q 12 hrs x 8 doses, Days 1-4
Prophylaxis: Antifungal & antibacterial therapy required beginning Day 5
G-CSF: 10µg/kg/day, SQ (total dose) in 1 or 2 injections beginning Day 14. Continue until PBSC collection completed or WBC >50,000/µL. Do not skip/reduce for bone pain.
STI571: 400mg, PO, BID (start after stem cell collection is complete until 72 hrs pre-transplant)
Leukapheresis will start when WBC >10,000/µL. Target is 5 x 106 CD34+ cells/kg. Send aliquot of each leukapheresis product for RT-PCR assay (via CALGB 9862).
Autologous PBSC Transplantation
Pt must remain in CR documented by normal BM w/<5% blasts w/i 2 wks of transplant and have stable or improving perip blood counts. ANC >500/µL & platelets >50,000/µL. PBSC transplant to take place >4 wks following hospital D/C and after recovery from myelosuppression toxicities. Gleevec must be stopped >72 hrs & <10 days pre-autologous transplant.
Allopurinol: 300mg, PO, QD, Days -9 through -2
Fractionated Total Body RT: Days -8 through -5 (1320cGy/11fx/120cGy each) over 4 days. 3fx/day will be given on Days -8 through -6 and 2fx/day on Day -5. Separate each fx by >4 hrs. Males will receive 400cGy boost to testes.
VP-16: 60mg/kg (corrected body wt), IV over 4 hrs, Day -4
Cyclophosphamide: 100mg/kg (corrected body wt), IV over 2 hrs, Day -2 (hydrate vigorously)
Autologous PBSC Transplant: Day 0
G-CSF: 5µg/kg/day (actual body wt), SQ, beginning Day 0 until ANC >1500/µL x 2 days or >5000/µL x 1 day.
(C): No Transplantation for Pts Who are NOT Transplant Candidates
Pts should NOT be removed from study. Will receive same high-dose Ara-C & VP-16 therapy for stem cell mobilization during autologous transplant, but will not have stem cells collected. Therapy to begin >72 hrs & <10 days following last dose of Gleevec in Course IV. Must have BM exam & RT-PCR assay (submit through CALGB 9862) on Day 30 following Course V.
VP-16: 10mg/kg/day (corrected body wt), CI over 96 hrs, Days 1-4 (total dose=40mg/kg)
Ara-C: 2000mg/m2, IV over 2 hrs, q 12 hrs, x 8 doses, Days 1-4
Prophylaxis: Antifungal & antibacterial therapy beginning Day 5
G-CSF: 10µg/kg/day, SQ (total dose) in 1 or 2 injections beginning Day 14. Continue until WBC >5000/µL. Do not skip/reduce for bone pain.
Course VI - Gleevec Maintenance Therapy
Allogeneic transplant pts: Gleevec, 400mg, PO, QD, beginning Day 30 post-transplant and continuing until 2 consecutive negative RT-PCR assays 3 mos apart are documented or until relapse.*
Autologous transplant pts: Gleevec, 400mg, PO, BID, beginning Day 30 post-transplant and continuing until 2 consecutive negative RT-PCR assays 3 mos apart are documented or until relapse.*
"No transplant" pts: Gleevec, 400mg, PO, BID, beginning Day 30 and continuing until 2 consecutive negative RT-PCR assays 3 mos apart are documented or until relapse.*
* All groups will have BM exams q 3 mos x 2 yrs, then q 6 mos x 3 yrs, and at relapse. Pts who do not achieve a negative RT-PCR assay and who do not relapse will continue Gleevec maintenance indefinitely. Pts who are RT-PCT negative prior to Course VI will continue therapy until a 2nd consecutive negative RT-PCR assay is documented.
Eligibility
Unequivocal histol dx of ALL.
Detection of t(9;22)(q34;q11) or 3-way variant by metaphase cytogenetics or BCR-ABL positive by molecular analysis (RT-PCR or FISH).
Complete or partial remission following 1 course of induction chemo w/intensive 4 or 5 drug regimen (w/ or w/o imatinib mesylate) on CALGB or SWOG protocol for previously untreated ALL pts. NOTE: Double induction regimen of SWOG S0333 is considered 1 course of induction chemo for purpose of this eligibility criterion.
OR
Complete or partial remission following 1 course of therapy on any standard induction regimen (w/ or w/o imatinib mesylate) w/o prior enrollment on a cooperative group frontline protocol. In these cases, documentation of Ph+ positivity may occur outside CALGB or SWOG lab. NOTE: CALGB institutions must enroll pts on CALGB 9862 and initial sample submission for the companion trial must occur at same time as enrollment on CALGB C10001. Enrollment on CALGB 8461 & 9665 is not required.
Age >15 and <60.
No >6 wks of prior imatinib mesylate during induction therapy b/f study enrollment.
No pregnant or nursing women. Men/Women of reproductive potential must use effective contraception until 3 mos after last dose of Gleevec.
PRESTUDY REQUIREMENTS (w/i 5 days pre-study):
H&P, pulse, BP, temp, ht, wt, BSA, perf status
Tumor msmts (liver, spleen, lymph nodes, & mediastinal mass [if applicable])
CBC/diff/platelets
Serum creat, BUN, lytes
PT, PTT
SGOT, SGPT, alk phos, bili, LDH
Uric acid, PO4
Total protein, albumin
EKG
µ-HCG or Serum HCG (if childbearing potential)
BM histol review
CXR (PA & Lat)
CSF cell count, CSF protein & glucose (as clinically indicated)
Cytogenetics
BM asp/bx
Signed informed consent.