CTSU E5508 - "Randomized Phase III Study of Maintenance Therapy with Bevacizumab, Pemetrexed, or a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and Bevacizumab for Advanced Non-Squamous NSCLC"

Treatment Plan     (Supplied Drug:  None)

STEP 1 - REGISTRATION

Induction Arm 1 (Cycles 1-4)

Paclitaxel:  200mg/m2, IV over 3 hrs, Day 1, q 21 days

Carboplatin:  AUC=6, IV over 15-30 mins, Day 1, q 21 days (immed following Paclitaxel IV)

Bevacizumab:  15mg/kg, IV over 30-90 mins, Day 1, q 21 days

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If PD à Long-Term Follow-up

If CR, PR, or SD à RANDOMIZATION

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STEP 2 - RANDOMIZATION

Maintenance (Cycles 1 & up; continue until progression or unacceptable toxicity.  Cycle = 21 days.)

Arm A

Bevacizumab:  15mg/kg, IV over 30-90 mins, Day 1, q 21 days

Arm B

Pemetrexed:  500mg/m2, IV over 10 mins, Day 1, q 21 days

Arm C

Pemetrexed:  500mg/m2, IV over 10 mins, Day 1, q 21 days

Bevacizumab:  15mg/kg, IV over 30-90 mins, Day 1, q 21 days (following Pemetrexed)

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Long-Term Follow-up

Eligibility

• Cytol- or histol-confirmed NSC lung cancer.

• Predominant non-squamous histology (NSCLC NOS is allowed).  Mixed tumors will be categorized by predominant cell type.  No small cell elements can be present.

• Stg IV (includes M1a, M1b, or recur disease) - according to 7th ed. of TNM classification system.  Pts w/T4NX (Stg IIIB) with nodule in ipsilateral lobe are eligible if they arer not candidates for combined chemo & RT.

• No prior malignancy w/i past 3 yrs except superficial melanoma, basal cell carcinoma, or carcinoma in situ.

• No prior systemic chemo for advanced lung cancer.

• Prior adjuv chemo is allowed if >12 mos between prior chemo administration & registration.

• >3 wks between completion of prior RT & regist.

• No prior use of Paclitaxel, Pemetrexed, or Bevacizumab.  Prior Carboplatin is allowed if given as part of adjuv chemo.

• Age >18.

• No brain mets.

• No major hemoptysis w/i 4 wks pre-regist (>1/2 teas bright red blood ).

• Within 2 wks pre-regist:  Leukocytes >3000/mm3; ANC >1500/mm3; platelets >100,000/mm3; total bili w/i INL; SGOT & SGPT each <3x IULN; creat <INL or CrCl >60mL/min/1.72m2 (normalized to BSA) for pts w/creat levels above instit normal; urine dipstick <0 - 1+ (If >1+, UPC is required & must be <1 for participation).

• No uncontrolled intercurrent illness (medical, psychiatric, social) that would limit study compliance.

• Must have meas or non-meas disease by RECIST.  Baseline msmts & eval of all sites of disease w/i 4 wks pre-regist.

• No hx of HTN unless adequately controlled (<150/100) w/anti-hypertensive meds or diet.

• ECOG perf status 0-1.

• No prior thrombotic events or major bleed w/i 12 mos pre-regist.

• Concomitant use of therapeutic anti-coagulation is allowed.

• No major surgery, major bx, or significant traumatic injury w/i 3 mos pre-regist.

• No core bx w/i 7 days pre-regist.

• No significant vascular disease w/i 6 mos pre-regist.

• No clinically significant vascular disease.

• No clinically significant cardiovascular disease.

• No prior abdominal fistula, GI perforation, or intra-abdominal abscess w/i 6 mos pre-regist.

• No prior serious non-healing wound, ulcer, or bone fx.

• No cavitary lesions in lungs.

• No pregnant or nursing women.  Women of reproductive potential must have negative blood pregnancy test w/i 2 wks pre-regist.

• Women/Men of reproductive potential must abstain from sexual intercourse or use effective contraception during study tx & >6 mos post-study drug completion.

• No HIV pts who are taking anti-retroviral therapy.

• PRESTUDY REQUIREMENTS:

  Within 4 wks pre-regist:  Scans & xrays used to assess all meas or non-meas disease

  Within 2 wks pre-regist:  All labwork

  • H&P, perf status, wt, ht, BP

  • EKG (if medically indicated)

  • CBC/diff/platelets (<24 hrs prior to tx cycle)

  • SGOT, SGPT, alk phos, bili, creat, blood urea nitrogen, Mg, Ca, Na, K, albumin, Cl, bicarb, & LDH (<24 hrs prior to tx cycle)

  • PT/PTT, INR

  • Serum pregnancy test (if applicable)

  • Imaging for tumor asmt (use same method throughout tx)

  • Urine dipstick for protein

  • Smoking status

  • Biological tissue collection (w/pt's consent)*

  *      PE tumor, two 10-mL K₂-EDTA tubes for plasma & residual cells (RBC & WBC), & two ACD tubes of perip blood.  Plasma & residual cells should be kept in

  -70^oC or colder freezer & shipped quarterly on dry ice (see protocol for alternative).  Ship all specimens to:  ECOG Path Coordinating Office - Reference Lab; Chicago, IL.  Obtain overnight courier acct number from ECOG-PCO.

• Signed informed consent.