CTSU E2905 - "Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) to Treatment with Lenalidomide (Revlimid) Alone and in Combination with Epoetin Alfa (Procrit) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia"

NOTE:  Each site must have two trained counselors available for counseling all patients receiving Lenalidomide.  Training is provided free by Celgene.  Training certificate must be provided to CTSU.  Lenalidomide may not be ordered until trained counselor information is provided.  See Appendix XIII for details.

Treatment Plan    (Supplied Drugs:  Lenalidomide & Epoetin Alfa)

DETERMINE if pt is del 5q 31.1

If del 5q 31.1 à REGISTRATION to Arm A

If not del 5q 31.1 à RANDOMIZATION

STEP 1 (q 28 days x 4 cycles)

Arm A

Lenalidomide:  10mg, PO, QD, x 21 days

Arm B

Lenalidomide:  10mg, PO, QD, x 21 days

Epoetin Alfa:  60,000 units, SC, q week

Arm A pts achieving MER

Continue Arm A tx until relapse/progression

At relapse:  Offer crossover to Arm B (STEP 2 REGISTRATION).  If pt doesn't cross over, pt will DC study tx.

Arm A pts not achieving MER

Offer crossover to Arm B (STEP 2 REGISTRATION).  If pt doesn't cross over, pt will DC study tx.

Arm B pts achieving MER

Continue Arm B tx until relapse/progression

Arm B pts not achieving MER

DC study tx

Eligibility

• Age >18.
• Documented MDS dx by WHO criteria (duration > 3 mos) or non-proliferative CMML (WBC <12,000/mcL).
• IPSS category low- or intermediate-1-risk disease.  IPSS score determined by cytogenetic analysis pre-randomiz.  Must have cytogenetic analysis done (to calculate IPSS).  If current BM bx is a dry tap, pts w/cytogenetic failure & <10% marrow blasts are eligible.  Pts w/cytogenetic failure must have previous cytogenetic results (FISH is not a substitute) w/i last 6 mos post-last type of MDS tx (not referring to growth factors as type of MDS tx).
• Symptomatic anemia untransfused w/Hgb <9.5g/dL <8 wks pre-randomiz or RBC transfusion-dependence (i.e., >2 units/mo) confirmed for <8 wks pre-randomiz.  NOTE:  For non-transfusion dependent pts (i.e., receiving <2 units/4 wks x 8 wks pre-study) who receive periodic transfusions, the mean 8-wk pre-transfusion Hgb should be used to determine protocol eligibility & response.
• NOTE:  Only for pts w/o the deletion of 5q31.1 - Must have failed tx w/erythropoietic growth factor or have low probability of response to rhu-erythropoietin.  These are defined as:
  • Prior erythropoietin failure:  Minimum trial of >40,000 units Epoetin Alfa/week x 8 wks or equiv dose of darbepoetin alfa  8 wks w/failure to achieve transfusion independence in dependent pts or failure to achieve >2g rise in Hgb sustained for >4 wks in non-transfusion dependent pts.
  • Low erythropoietin response profile:  rhu-erythropoietin & epoetin alfa-naive pts receiving >2U pRBC/mo for minimum of 8 wks, & serum erythropoietin >500mU/mL in 8 wks pre-randomiz for a Hgb <9.5g/dL.
• Off all non-transfusion therapy for MDS for 28 days pre-initiation of study tx, including all type of growth factors.  May receive hydrocortisone prophylactically to prevent transfusion reactions.
• Serum erythropoietin documented pre-randomiz & <56 days b/f Day 1 of study tx.  NOTE:  Hgb must be <9.5g/dL at time serum erythropoietin is drawn.
• No documented iron deficiency.  Must have documented marrow iron stores.  If marrow iron stain not available, transferin saturation must be >20% or serum ferritin >100ng/mL.
• No pregnant or nursing women.  Females of childbearing potential (see protocol definition) must have 2 negative pregnancy tests (sensitivity >25 mIU/mL) - w/i 10-14 days & again w/i 24 hrs prior to starting Cycle 1 of Lenalidomide.
• Pts must use effective contraception & must agree to counseling by a trained counselor q28days about pregnancy precautions/risks.  Women/Men of reproductive potential (including males w/vasectomies) must commit to continued abstinence from heterosexual intercourse or use 2 acceptable methods of contraception for >28 days b/f starting Lenalidomide, during Lenalidomide therapy, during dose interruptions, & >28 days post Lenalidomide therapy (see protocol for details).
• No prior therapy w/Lenalidomide.
• No uncontrolled seizures or uncontrolled HTN.
• No MDS secondary to tx w/RT, chemo, &/or immunotherapy for malignant or autoimmune diseases.
• Documented on 2 occasions w/i 21 days pre-randomiz (must be separated by >7 days); at least 1 of 2 CBC/diffs & chem testing (including LFTs) must be done w/i 7 days of regist:  Platelets >50,000/mcL w/o platelet transfusion; ANC >500 cells/mcL (ANC >500/mcL w/o myeloid growth factor); serum creat <1.5x ULN; serum SGOT or SGPT <2.0x ULN; serum total bili <3.0 mg/dL.
• Prior thalidomide is allowed, but must not have prior >Grade 3 allergic reactions to thalidomide.
• No prior desquamating rash from Thalidomide at study entry.
• No clinically significant anemia resulting from iron, B12, or folate deficiencies, autoimmune or hereditary hemolysis, or GI bleeding.
• No use of cytotoxic chemo agents or experimental agents (not commercially available) for tx of MDS w/i 8 wks pre-randomiz.
• No hx of malignancy other than MDS (except non-melanoma skin cancer or in situ cervix or breast cancer) unless confirmed disease-free >3 yrs.
• No serious medical condition, unstable medical co-morbidity, or psychiatric illness to preclude informed consent or will place subject at unacceptable risk w/study participation.
• No hx of thrombo-embolic events w/i 3 yrs pre-randomiz.
• No known HIV-1 seropositivity.
• No known allergic reaction to epoetin alfa (Procrit) or human serum albumin.

• PRESTUDY REQUIREMENTS (56 days pre-randomiz unless otherwise noted)

  1)  All CBCs & RBC transfusion values for 8 wks pre-randomiz are required to establish transfusion-dependence & baseline Hgb.

  2)  For non-transfusion dependent pts who receive periodic transfusions, the mean pre-transfusion Hgb should be used to determine eligibility & response reference.

  3)  Prestudy CBC w/diff & chemistries w/i 21 days pre-randomiz (2 occasions must be separated by >7 days).

  4)  All required prestudy chemistries (1 of 2 required sets) w/i 7 days pre-randomiz.

  5)  Prestudy non-transfused Hgb, Hct, WBC, ANC, & platelets should be documented on 2 occasions over 56 days pre-randomiz (separated by >7 days).

  • Medical hx
  • Prior MDS tx
  • ECOG perf status
  • Pregnancy test (if applicable, serum or urine ß-HCG w/sensitivity >25mIU/mL)*
  • Physical exam (repeat on Day 1)
  • ECG
  • TSH, T3, & T4
  • Serum erythropoietin (when Hgb <9.5g/dL pre-study)
  • Serum chemistry (w/i 21 days pre-regist)**@$
  • Hematology (pre-study CBC w/diff) @$

  • RBC transfusion hx***

  • BM aspir/bx (w/cytogenetic analysis & iron stains)

  • Diagnostic slides/smears (MANDATORY)#

  • BM bx block (w/pt's consent; may submit 5 unstained BM bx level slides if block can't be submitted)^

  • Perip blood - two 10mL sodium/heparin tubes (w/pt's consent)^

  • BM aspir (w/pt's consent; 5 mL EDTA+ tube)^

  • Karyotypes (MANDATORY)##

  • Education & Counseling (Day 1, Cycle 1)$$

  *     Within 10-14 days prior to start of study drug & again w/i 24 hrs of start of study drug

  **     Na, K, Cl, CO2, Ca, Mg, phosphorus, BUN, creat, glucose, albumin, total protein, alk phos, total bili, SGOT or SGPT, LDH, & uric acid

  ***   RBC, Hgb, Hct, WBC, diff, ANC, & platelets required for protocol therapy must be done <24 hrs prior to tx cycle.

  #       2 stained BM smears (to include 1 Wright-Giemsa stain & 1 Iron Stain), 1 H&E stained BM bx slide, & 1 Wright-Giemsa stained perip blood smear.  Submit w/i 1 mo of regis to ECOG PCO.

  ##    Submit 2 original karyotypes to Mayo Clinic Cytogenetics Lab.

  @     Both sets of CBC/diffs & chemistries should be collected after pt signs consent.

  $       At least 1 of 2 required sets should be done w/i 7 days of randomiz.

  ^       Submit initial BM aspir to Dr. Alan List's lab (call prior to shipping for courier acct #).  Should be shipped on Mon-Thurs only.

  $$    Lenalidomide Counseling & Education Document (Appendix XI) must be completed by a trained counselor at tx site prior to each dispensing of Lenalidomide.  Only enough Lenalidomide for 28 days or 1 cycle (whichever is shorter) may be dispensed to pt each cycle.

• Signed informed consent.