CALGB 40502/CTSU 40502 A randomized phase III trial of weekly paclitaxel compared to weekly nanoparticle albumin bound nabpaclitaxel or ixabepilone combined with bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer Activated CALGB: October 13, 2008 Study Chairperson: H. Rugo Accrual as of 4/16/2009: 31 Statisticians: W. Barry Projected Accrual: 900 C. Cirrincione Projected Closure: October 2011 Data Coordinator: P. Kartcheske Current Protocol Update: Original SCHEMA Stratification Factors Taxane as adjuvant therapy: 1) Yes 2) No ER/PgR status: 1) Either ER or PgR Positive R A N D O M Arm A Paclitaxel 90 mg/m 2 IV weekly days 1, 8, 15 + bevacizumab 10 mg/kg IV days 1 & 15 q cycle Arm B Nab-paclitaxel 150 mg/m 2 weekly days 1, 8, 15 + bevacizumab 10 mg/kg IV days 1 & 15 q cycle Restage q 2 cycles until disease progression CR, PR, SD continue study tx until PD 2) Both ER and PgR Negative I Z E Arm C Ixabepilone 16 mg/m 2 weekly days 1, 8, 15 + bevacizumab 10 mg/kg IV days 1 & 15 q cycle A cycle is defined as 28 days Objectives Primary To compare the progression-free survival (PFS) in patients with metastatic breast cancer receiving nab-paclitaxel versus paclitaxel (control arm), and to separately compare PFS in patients receiving ixabepilone versus paclitaxel. Treatment will include concomitant bevacizumab in all three arms. Secondary 1. To compare the objective response rate, duration of response, and time to treatment failure in patients receiving nab-paclitaxel versus paclitaxel, and to separately compare these endpoints in patients receiving ixabepilone versus paclitaxel. 2. To compare the 12-month rate of progression in patients receiving nab-paclitaxel versus paclitaxel, and to separately compare this endpoint in patients receiving ixabepilone versus paclitaxel. 3. To determine toxicities in patients receiving nabpaclitaxel as compared to paclitaxel, and in patients receiving ixabepilone as compared to paclitaxel. In particular, the rates of grade 3/4 sensory neuropathy and the rates of peripheral neuropathy assessed by the FACT/GOG Neurotoxicity subscale will be determined. 4. To compare overall survival in patients receiving nab-paclitaxel versus paclitaxel, and to separately compare overall survival in patients receiving ixabepilone versus paclitaxel. 5. To evaluate the relationships between SPARC overexpression and changes in blood levels of caveolin-1 (Cav-1) to PFS and secondary endpoints of response during treatment with nabpaclitaxel as compared to paclitaxel, and with ixabepilone compared to paclitaxel. 6. To evaluate the relationships between changes in blood levels of circulating tumor cells (CTCs) and circulating endothelial cells (CECs) to PFS and secondary endpoints of response during treatment with nab-paclitaxel as compared to paclitaxel, and with ixabepilone compared to paclitaxel. Breast - 31
7. To evaluate the association of expression levels of the microtubule associated proteins tau and beta tubulin isotype composition with PFS and secondary endpoints of response during treatment with nab-paclitaxel as compared to paclitaxel, and with ixabepilone compared to paclitaxel. 8. To investigate a potential CYP2C8*2/*3 by paclitaxel interaction with respect to PFS. 9. To determine if CYP2C8*2 and CYP2C8*3 are associated with paclitaxel-induced peripheral neuropathy. 10. To perform exploratory analysis of CYP3A4, CYP3A5, ABCB1 and ABCC2 polymorphisms with response and toxicity profiles. 11. To prospectively collect data on sociodemographics, non-cancer morbidities, and receipt of post-trial therapy to evaluate the role of potential disparities on survival from cancer. Required Laboratory Values Granulocytes Platelet Count Creatinine Bilirubin AST, ALT Serum or urine Urine protein β-hcg Stratification 1. Taxane as adjuvant therapy Yes No 2. ER/PgR status Either ER/PgR positive Both ER and PgR negative Administrative Comments >1,500/µl > 100,000/µl < 2.0 mg/dl < 1.5 x ULN unless due to Gilbert s syndrome 2.5 x ULN Negative in premenopausal women of child-bearing potential This study was activated on October 13, 2008. Eligibility Criteria Histologic confirmation of invasive cancer of the breast; Stage IV or Stage IIIB disease (using AJCC criteria, 6th edition) not amenable to local therapy. No concurrent active secondary malignancy (see Section 4.3 of the protocol) HER2+ disease allowed if pt received prior trastuzumab or lapatinib therapy. HER-2/neu status must be known at the time of study registration. ER and/pgr status must be known at the time of registration 18 years of age Prior treatment: adjuvant or neoadjuvant taxane allowed (see Section 4.7.1 of the protocol), no prior chemotherapy for metastatic or locally advanced disease, prior radiation allowed (see Section 4.7.3 of the protocol); prior tx with bevacizumab allowed Bisphosphonate therapy allowed (see Section 4.7.4 of the protocol) No major surgery allowed within 28 days prior to registration (see Section 4.8 of the protocol) Patients must have measurable disease (see Section 4.9 of the protocol) Patients may not have pre-existing peripheral neuropathy > grade 2 ECOG (Zubrod) PS 1; life expectancy 12 wks Patients must not be pregnant or nursing No history of hypersensitivity CTCAE grade > 3 to paclitaxel or Cremophor No recent history of abdominal fistula, or intraabdominal abscess, GI perforation or significant bleeding episodes (see Sections 4.14-4.16 of the protocol) No history of clinically significant cardiovascular disease Anticoagulation therapy allowed No history of stroke or TIA within 6 months prior to registration Patients with a history of seizures must be well controlled with standard medication No CNS metastases or leptomeningeal disease No serious, non-healing wounds, ulcer or bone fracture Breast - 32
Accrual Besides CALGB, this study is open through the CTSU network. As of April 16, 2009, 31 patients have registered to this study. Sixteen (16) patients were entered by the CALGB and 15 via the CTSU. Accrual by Institution For Period 10/13/2008 Through 4/16/2009 Main/At-Large Member Affiliate Total GEORGE 2 0 2 GRAND 0 1 1 IORA 0 3 3 KCCOP 1 0 1 MSH 0 1 1 MVCC 0 1 1 NICRC 0 1 1 OSUMC 2 0 2 SIBLEY 2 0 2 WASH-BARN 2 0 2 CALGB Total 9 7 16 CTSU 15 Total Accrual 31 Accrual by Month 2008 2009 Total Jan -- 6 6 Feb -- 9 9 Mar -- 7 7 Apr -- 6 6 May -- -- -- Jun -- -- -- Jul -- -- -- Aug -- -- -- Sep -- -- -- Oct 0 -- 0 Nov 1 -- 1 Dec 2 -- 2 Total 3 28 31 Adverse Events The table below details adverse events of Grade 3 or higher severity that were possibly, probably or definitely due to protocol treatment. Adverse event data were available for 21 patients. Hematologic Adverse Events Blood/Bone Marrow Breast - 33 Hemoglobin A=Pac 1 ( 14%) 0 ( 0%) 0 ( 0%) 7 Leukocytes (total WBC) A=Pac 1 ( 14%) 0 ( 0%) 0 ( 0%) 7 Neutrophils/granulocytes (ANC/AGC) A=Pac 1 ( 14%) 0 ( 0%) 0 ( 0%) 7 Maximum Hematologic AE A=Pac 2 ( 29%) 0 ( 0%) 0 ( 0%) 7
Non-Hematologic Adverse Events Gastrointestinal Breast - 34 Anorexia A=Pac 0 ( 0%) 0 ( 0%) 0 ( 0%) 7 Dehydration A=Pac 0 ( 0%) 0 ( 0%) 0 ( 0%) 7 Diarrhea A=Pac 0 ( 0%) 0 ( 0%) 0 ( 0%) 7 Nausea A=Pac 0 ( 0%) 0 ( 0%) 0 ( 0%) 7 C=Ixa 2 ( 25%) 0 ( 0%) 0 ( 0%) 8 Vomiting A=Pac 0 ( 0%) 0 ( 0%) 0 ( 0%) 7 Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area Neurology Pain A=Pac 0 ( 0%) 0 ( 0%) 0 ( 0%) 7 Seizure A=Pac 0 ( 0%) 0 ( 0%) 0 ( 0%) 7 Arthralgia (joint pain) A=Pac 0 ( 0%) 0 ( 0%) 0 ( 0%) 7 Pulmonary/Upper Respiratory Vascular Dyspnea (shortness of breath) A=Pac 0 ( 0%) 0 ( 0%) 0 ( 0%) 7 Pneumonitis/pulmonary infiltrates A=Pac 0 ( 0%) 0 ( 0%) 0 ( 0%) 7 Thrombosis/thrombus/embolism A=Pac 0 ( 0%) 0 ( 0%) 0 ( 0%) 7 B=Nab 0 ( 0%) 1 ( 17%) 0 ( 0%) 6
Maximum Non-Hematologic AE A=Pac 0 ( 0%) 0 ( 0%) 0 ( 0%) 7 B=Nab 1 ( 17%) 1 ( 17%) 0 ( 0%) 6 C=Ixa 4 ( 50%) 0 ( 0%) 0 ( 0%) 8 Maximum Overall AE A=Pac 2 ( 29%) 0 ( 0%) 0 ( 0%) 7 B=Nab 2 ( 33%) 1 ( 17%) 0 ( 0%) 6 C=Ixa 4 ( 50%) 0 ( 0%) 0 ( 0%) 8 Breast - 35