Breast Program. Scientific Coordinator: Edith A Perez, MD. Community Co-Chair: Kendrith M Rowland Jr, MD Lead Statistician: Amylou C Dueck, PhD

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1 Breast Program Scientific Coordinator: Edith A Perez, MD Community Co-Chair: Kendrith M Rowland Jr, MD Lead Statistician: Amylou C Dueck, PhD Studies Open for Patient Enrollment Spring 2011 I. Surgery A. ACOSOG Z1031: A Randomized Phase III Trial Comparing 16 to 18 Weeks of Neoadjuvant Exemestane (25 mg daily), Letrozole (2.5 mg), or Anastrozole (1 mg) in Postmenopausal Women with Clinical Stage II and III Estrogen Receptor Positive Breast Cancer. Available through the CTSU. Coordinating center is ACOSOG. B. ACOSOG Z1071: A Study Evaluating the Role of Sentinel Lymph Node Surgery and Axillary Lymph Node Dissection Following Preoperative Chemotherapy in Women with Node Positive Breast Cancer (T1-4, N1-2, M0) at Initial Diagnosis. Available through the CTSU. Coordinating center is ACOSOG. II. Radiation A. NSABP B-39 / RTOG 0413: A Randomized Phase III Study of Conventional Whole Breast Irradiation (WBI) Versus Partial Breast Irradiation (PBI) for Women with Stage 0, I or II Breast Cancer. To evaluate standard vs partial breast RT. Available through the CTSU. Coordinating centers are NSABP/RTOG. III. Adjuvant Therapy A. Monoclonal Antibody 1. N063D / BIG 2-06 ALTTO: Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation Study - A randomized, multi-centre, open-label, phase III study of adjuvant lapatinib, trastuzumab, their sequence and their combination in patients with HER2 positive primary breast cancer. Design 2B (targeted therapy with nonanthracycline chemotherapy and docetaxel) remains open for pre-registration IN NORTH AMERICA ONLY. Preregistration is expected to close in June 2011 with subsequent closure of randomization shortly thereafter. Four arm trial testing different anti-her2 approaches. Extensive quality of life and translational components: frozen tissue, genomics, proteomics, circulating tumor cells. Available through the CTSU. Coordinating centers are NCCTG/BIG.

2 B. Bisphosphonates, Hormonal Therapy, and Genomic Profiling Adjuvant Trials 1. S1007: A Phase III Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- Chemotherapy in Patients with 1-3 Positive Nodes, Hormone Receptor- Positive and HER2-Negative Breast Cancer with Recurrence Score (RS) of 25 or Less. Available through the CTSU. Coordinating center is SWOG. C. Chemotherapy 1. S0221: Phase III trial of 2 schedules of AC followed by paclitaxel (+ G-CSF) q2w vs. weekly paclitaxel. Also known as dose dense vs. denser chemotherapy. Available through the CTSU. Coordinating center is SWOG. IV. Stage III V. Stage IV 1. N0733: Phase II trial of capecitabine and lapatinib with or without IMC-A12 in patients with HER2 positive breast cancer previously treated with trastuzumab and an anthracycline and/or a taxane. Translational components: tissue markers, circulating tumor cells, serum markers. Sites receive 1.0 Treatment Credit plus 0.5 Cancer Control Credit for the quality of life study in this protocol. Available through the CTSU. Coordinating center is NCCTG. 2. N063H / CALGB 40502: Randomized phase III trial comparing the combination of weekly ixabepilone versus weekly paclitaxel versus weekly nab-paclitaxel (with bevacizumab) in patients with previously untreated MBC. Available through the CTSU. Coordinating centers are CALGB and NCCTG. 3. N0937: Phase II Trial of Brostallicin and Cisplatin in Patients with Refractory Metastatic Triple Negative Breast Cancer. 4. N093B: Phase I/II Study of LBH589 and Letrozole in Post-Menopausal Women with Basal-Like (Triple Negative) Aromatase Inhibitor Refractory Metastatic Breast Cancer. Phase II expected to open to NCCTG in Summer N1031: Randomized Phase II Study of Two Doses of Pixantrone for Patients with Metastatic Breast Cancer. 6. S0500: A Randomized Phase III Trial to Test the Strategy of Changing Therapy Versus Maintaining Therapy for Metastatic Breast Cancer Patients Who Have Elevated Circulating Tumor Cell Levels at First Follow-up Assessment. Available through the CTSU. Coordinating center is SWOG.

3 VI. Patient-reported Outcomes 1. N063DSS3: Measuring the interference of diarrhea, rash, fatigue, and oral adherence in the daily lives of patients taking lapatinib and/or trastuzumab as part of adjuvant treatment for breast cancer enrolled on the ALTTO Study through the NCI CTEP CTSU. Substudy of N063D ALTTO available through the CTSU. Coordinating center is NCCTG. Proposed Studies at Different Stages of Review 1. N1131: Phase II Trial of AFP-464 in Patients with Metastatic Estrogen Receptor (ER) Positive Breast Cancer. 2. N1132: Randomized Phase II Study of Combination Ombrabulin and Docetaxel in the First or Second Line Metastatic Breast Cancer Setting. 3. N1134: Phase III, Randomized Trial of Ablative Therapy Versus Best Medical Therapy as Initial Treatment for Oligometastatic Stage IV Breast Cancer. 4. S0800: A Randomized Phase II Trial of Weekly Nanoparticle Albumin Bound Paclitaxel (Nab-Paclitaxel) (NSC736631) With or Without Bevacizumab, Either Preceded by or Followed by Q 2 Week Doxorubicin (A) and Cyclophosphamide (C) Plus Pegfilgrastim (Peg-G) as Neoadjuvant Therapy for Inflammatory and Locally Advanced HER-2/Neu Negative Breast Cancer. Will be available through the CTSU.

4 NCCTG Status Report for Study N063D May 2011 BIG 2-06/N063D, ALTTO: Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation Study - A randomised, multi-centre, open label, phase III study of adjuvant lapatinib, trastuzumab, their sequence and their combination in patients with HER2/ErbB2 positive primary breast cancer Purpose of Study: - Primary Goal 1) To compare disease-free survival (DFS) in patients with HER2 overexpressing and/or amplified breast cancer randomized to trastuzumab for one year versus lapatinib for one year versus weekly trastuzumab (12 or 18 weeks, according to assigned design) followed by a six-week washout period followed by lapatinib (28 or 34 weeks, according to assigned design) versus trastuzumab in combination with lapatinib for one year. - Secondary Goals 1) To compare overall survival, time to recurrence, time to distant recurrence, and cumulative incidence of brain metastases as the site of first breast cancer recurrence among the four treatment groups. 2) To evaluate safety and tolerability of the four regimens. 3) To conduct all analyses separately for cohorts defined by cmyc, PTEN, and p95 status. Study Chair: Edith A Perez MD Statistician: Amylou C Dueck PhD Projected Number of Patients: 8400

5 Study Design: This is a randomized, open label multi-centre phase III study comparing the activity of lapatinib alone versus trastuzumab alone versus trastuzumab followed by lapatinib versus lapatinib concomitantly with trastuzumab in the adjuvant treatment of patients with ErbB2 over-expressing and/or amplified breast cancer. Patients will be enrolled according to one of two design schemas, with Design 2 having two chemotherapy options (Design 2 and 2B), and will be randomized to one of four treatment regimens within each design schema Design 1: Sequential administration of targeted therapy following completion of chemotherapy. Design 2: Post AC paclitaxel or docetaxel concurrent with targeted agents. Design 2B: Non-anthracycline option: concurrent administration of targeted therapy with docetaxel/carboplatin. The primary objective of this study is to compare disease-free survival (DFS) in patients with HER2 overexpressing and/or amplified breast cancer randomized to trastuzumab for one year versus lapatinib for one year versus trastuzumab (12 or 18 weeks, according to assigned design) followed by a six-week treatment-free interval followed by lapatinib (28 or 34 weeks, according to assigned design) versus trastuzumab in combination with lapatinib for one year (52 weeks). Study Status/ Accrual: This study opened on 2/11/2008 and worldwide has accrued 8277 of a targeted 8400 patients as of 3/22/2011. CTSU accrual was 692 patients: NCCTG 260 (38%), CALGB 121 (17%), CTSU 12 (2%), ECOG 127 (18%), NSABP 24 (3%), RTOG 9 (1%), SWOG 96 (14%), ACOSOG 7 (1%), GOG 1 (0.1%), NCIC CTG 35 (5%). Design 1 (sequential administration of targeted therapy following completion of chemotherapy) was closed to accrual in March 2009 due to the accrual imbalance between Design 1 and Design 2 (concurrent administration of targeted therapy with chemotherapy). Accrual to Design 2 (post AC paclitaxel or docetaxel concurrent with targeted agents) was closed on March 31, Design 2B (non-anthracycline option: concurrent administration of targeted therapy with docetaxel/carboplatin) remains open for accrual in the US and Canada but pre-registration for Design 2B is expected to close in June 2011.

6 NCCTG Status Report for Study N063I May 2011 Changes in Breast Density and Plasma Hormone Levels After One Year of Aromatase Inhibitor Therapy Purpose of Study: Design Schema: 1) To assess the changes in percent breast density in response to one year of aromatase inhibitor therapy from levels prior to the initiation of treatment. 2) To assess the changes in dense area in response to one year of aromatase inhibitor therapy from levels prior to the initiation of treatment. 3) To examine whether changes in percent breast density in response to one year of aromatase inhibitor therapy from pre-treatment levels correlate with changes in plasma hormones (estrone, estrone-sulfate, estradiol, SHBG) and drug levels (anastrozole or exemestane) over the same time period. 4) To examine whether changes in dense area in response to one year of aromatase inhibitor therapy from pre-treatment mammogram correlate with changes in plasma hormones (estrone, estrone-sulfate, estradiol, SHBG) drug levels (anastrozole or exemestane) over the same time period. 5) To assess whether women with high pre-treatment dense area (upper tertile) experience greater decreases in percent breast density after one year of aromatase inhibitor therapy than women with low pre-treatment percent density (lower tertile). 6) To assess whether women with high pre-treatment dense area (upper tertile) experience greater decreases in dense area after one year of aromatase inhibitor therapy than women with low pre-treatment dense area (lower tertile). Registration Observe for one year while receiving aromatase inhibitor therapy Materials to be submitted include: Blood sample collected prior to and 1 year post treatment Signed authorization form to release mammograms taken prior to and 1 year post treatment Patient Questionnaire completed prior to start of treatment Study Chair: Statistician: Projected Number of Patients: Treating Schedule: Celine M. Vachon Ph.D. Vera Suman Ph.D. 250 This is an observational trial.

7 Study Design: Study Status/ Accrual: Adverse Events: This observational study enrolls post-menopausal women with ER positive and/or PR positive breast cancer who have completed surgery +/- chemotherapy and will begin aromatase inhibitor therapy. Prior to and one year after starting AI therapy, mammograms and blood draws will be taken to assess changes in breast density and plasma hormone levels. This study was opened on 11/16/2007 and was closed on 11/07/2008 with a final accrual of 140 patients. There were 3 patient cancellations during the course of the study, and 1 patient was deemed ineligible. There are no AEs to report as this was an observational trial.

8 NCCTG Status Report for Study N093B - May 2011 Phase I/II Study of Panobinostat (LBH589) and Letrozole in Patients with Triple Negative Metastatic Breast Cancer Purpose of Study: Phase I Primary: To determine the safety and maximum tolerated dose (MTD) of LBH589 in combination with letrozole 2.5 mg PO daily men and women with metastatic breast cancer. Secondary: To assess the therapeutic effects (confirmed response rate) of LBH589 in combination with letrozole in men and women with metastatic breast cancer. Phase II Primary: To assess the confirmed response rate (as determined by RECIST criteria) and safety profile of LBH589 in combination with letrozole in men and post-menopausal women with metastatic, triple negative breast cancer. Secondary: To examine the duration of response, clinical benefit rate, time to treatment failure, time to progression, progression-free survival, and overall survival in men and post-menopausal women treated with LBH589 in combination with letrozole who have triple negative metastatic breast cancer. Translational Research: 1) To examine the estrogen, progesterone, and HER2 status of tumor at primary compared to metastatic tissue, and if possible after treatment 2) As part of ongoing research for NCCTG breast studies, we are banking paraffin embedded tissue blocks/slides and blood products for future studies. Design Schema: Study Chair: Statistician: Projected Number of Patients: Registration LBH589 PO Days MWF of each week Letrozole PO Days 1-28 Winston Tan, M.D Edith A. Perez, M.D (NCCTG) Jake Allred, M.S 48

9 Treating Schedule: Study Design: Study Status/ Accrual: Agent Dose Route Days Re-treat LBH589 Assigned orally MWF every 4 weeks Letrozole 2.5 mg orally Days 1-28 every 4 weeks This is a Phase I/II study in patients with triple negative metastatic breast cancer treated with a combination of LBH589 and letrozole. The Phase I portion of this study is designed to determine the maximum tolerated dose (MTD) of a combination of LBH589 and letrozole in patients with metastatic breast cancer (any ER, PR, and HER2 level acceptable). The Phase II portion of this study will use a two-stage three-outcome design to assess the efficacy of LBH589 and letrozole in patients with ER-, PR-, and HER2- (triple negative) metastatic breast cancer. This study opened to the Phase I portion of the study on September 3, 2010, and has accrued 5 of a targeted maximum of 18 patients for the Phase I portion. The study is open to dose level 2 (30 mg) as of March 24, Adverse Event Summary: Adverse event data is available for all 3 patients accrued to the Phase I dose level 1 (20 mg) of the study. All three patients experienced at least one grade 3 adverse events, but no grade 4 adverse events or dose limiting toxicities were experienced. The grade 3 adverse events included thrombocytopenia (2), neutropenia (1), hypocalcemia (1), and hyponatremia (1) all thought to be at least possibly related to treatment and bladder infection (1) thought not to be related to treatment.

10 Table 1: Adverse Event Summary Phase I N % Patients with at least one: Arm Grade 3+ Adverse Event A Grade 3+ Hem Adverse Event A Grade 3+ Non-Hem Adverse Event A Grade Adverse Event N % N % N % N % Type Arm PLATELET COUNT DECREASED A WHITE BLOOD CELL DECREASED A ANEMIA A HYPERMAGNESEMIA A HYPOCALCEMIA A NEUTROPHIL COUNT DECREASED A ABDOMINAL PAIN A BLADDER INFECTION A CREATININE INCREASED A FATIGUE A HYPOKALEMIA A HYPONATREMIA A PERIPHERAL SENSORY NEUROPATHY A

11 NCCTG Status Report for Study N0434 May 2011 The Association of Breast Density Changes, Plasma Hormone Changes, and Breast Cancer Recurrence : A Companion Study To NCIC CTG MA.27 Purpose of Study: Design Schema: Study Chair: Statistician: Projected Number of Patients: Treating Schedule: Primary : 1) To assess the change in percent breast density in response to aromatase inhibitor therapy from levels prior to the initiation of treatment through 2 years of therapy. 2) To assess the change in dense area in response to aromatase inhibitor therapy from levels prior to the initiation of treatment through 2 years of therapy. 3) To examine whether changes in percent breast density in response to aromatase inhibitor therapy from pre-treatment to 1-year correlate with changes in plasma hormones (estrone, estrone-sulfate, estradiol, SHBG) and drug levels (anastrozole or exemestane) over the same time period. 4) To examine whether changes in dense area in response to aromatase inhibitor therapy from pre-treatment to 1-year correlate with changes in plasma hormones (estrone, estrone-sulfate, estradiol, SHBG) and drug levels (anastrozole orexemestane) over the same time period. 5) To examine the associations of haplotype tagged SNPs in genes in the aromatase pathway with changes in percent and area density, plasma hormone levels and 1-year drug levels. Secondary : 1) To assess whether women with high pre-treatment percent density (upper tertile) experience greater decreases in percent breast density at one and two years of aromatase inhibitor therapy than women with low pre-treatment percent density (lower tertile). 2) To assess whether women with high pre-treatment dense area (upper tertile) experience greater decreases in dense area at one and two years of aromatase inhibitor Registration Patients must be registered to the parent protocol, MA.27 before registering onto this companion study. Celine M. Vachon Ph.D. James N. Ingle M.D. Philip J. Stella M.D. Vera Suman Ph.D. 550 Treatment per randomized assignment on MA.27.

12 Study Design: This is a companion study of MA.27 assessing changes in breast density in response to aromatase inhibitor therapy. Participation requires the submission of: patient authorization for retrieval of mammograms taken at pre-, 1 year post-, and 2 years post- registration; submission of a blood specimen pre- and 1 year postregistration; and completion of a questionnaire at 1 year post- and 2 years postregistration. Study Status/ Accrual: Adverse Events: This study was opened on 12/08/2005 and was closed on 07/31/2008 with a final accrual of 575 patients. There were 2 patient cancellations during the course of the study, and 14 patients were deemed ineligible. There are no AEs to report as this was an observational trial.

13 NCCTG Status Report for Study N0539 May 2011 Phase II Trial of Fulvestrant and Bevacizumab in Patients with Metastatic Breast Cancer Previously Treated with an Aromatase Inhibitor Purpose of Study: Primary Endpoint To evaluate the 6-month progression-free survival rate of fulvestrant and bevacizumab in patients with metastatic breast cancer previously treated with an aromatase inhibitor. Secondary Endpoints 1. To describe the adverse event profile of fulvestrant and bevacizumab in patients with metastatic breast cancer previously treated with an aromatase inhibitor (adverse events graded using the NCI CTCAE version 3.0). 2. To describe the progression-free survival of patients receiving fulvestrant and bevacizumab. 3. To describe the overall survival of patients receiving fulvestrant and bevacizumab. 4. To describe the confirmed response rate of patients with measurable disease receiving fulvestrant and bevacizumab. 5. To describe the duration of response in patients with measurable disease receiving fulvestrant and bevacizumab. 6. To describe the time to treatment failure in patients receiving fulvestrant and bevacizumab. 7. To describe the time to first cytotoxic agent in patients receiving fulvestrant and bevacizumab. 8. To describe the QOL of patients receiving fulvestrant and bevacizumab. Translational Research 1. To explore angiogenesis markers in plasma and serum, at baseline and serially, and correlate with the antitumor activity of fulvestrant plus bevacizumab. 2. To investigate whether pretreatment tissue levels of angiogenesis and estrogen related pathways correlate with the antitumor activity of fulvestrant plus bevacizumab. As part of ongoing research for NCCTG breast studies, we are banking paraffin embedded tissue blocks/slides and blood products for future studies. Schema: Study Chair: Statistician: Register: Fulvestrant + Bevacizumab Winston Tan MD Kendrith Rowland MD Amylou C Dueck PhD

14 Projected Number of Patients: 51 Treating Schedule: Agent Dose Level Route Day ReRx fulvestrant 250 mg IM 1 28 days bevacizumab 10 mg/kg IV 1, days Study Design: This protocol will assess the efficacy of fulvestrant and bevacizumab in patients with metastatic breast cancer previously treated with an aromatase inhibitor using a two-stage phase II study design. STAGE 1: Enter 20 evaluable patients into the study. If 11 or fewer 3- month** progression-free survivors are observed in the first 20 evaluable patients, we may consider this regimen ineffective in this patient population and terminate this study. Otherwise, if the number of 3-month** progression-free survivors is at least 12, we will proceed to Stage 2. A 3-month** progression-free survivor is a patient who is on study treatment 3 months from registration without a documentation of disease progression. STAGE 2: Enter an additional 27 evaluable patients into the study. If 20 or fewer successes are observed in the first 47 evaluable patients, we may consider this regimen ineffective in this patient population. If 21 or more successes are observed in the first 47 evaluable patients, we may recommend further testing of this regimen in subsequent studies in this population. ** Note: The interim analysis used 3-month instead of 6-month progressionfree survival (as pre-specified in the protocol) so that the analysis could be completed in a timely fashion while accrual remained open. A preliminary pilot study of 5 patients treated for a minimum of one cycle will be performed to determine whether or not the proposed combination of fulvestrant and bevacizumab is a safe regimen. The regimen will be deemed safe if no grade 3 or higher bleeding at site of IM injection is noted in 5 out of 5 patients. Study Status/ Accrual: This study was opened on 09/26/2007 and was closed on 12/19/2009 with a final accrual of 36 patients. There were 2 patient cancellations during the course of the study, and 1 patient was deemed ineligible.

15 Adverse Events: There has been one patient who experienced grade 5 intracranial hemorrhage and grade 4 ischemia cerebrovascular which were deemed probably related to the study treatment. Four other grade 4 adverse events were reported: hypertension deemed probably related, confusion deemed possibly related, disseminated intravascular coagulation deemed unlikely related and left ventricular failure deemed not related. The following grade 3 adverse events were reported: anemia (1 patient), hypertension (2 patients) and proteinuria (1 patient) which were definitely related to treatment; vaginal hemorrhage, thrombosis, dermatology and proteinuria (1 patient each) which were probably related to treatment; confusion, dehydration, encephalopathy, fatigue, catheter infection, insomnia, weight loss, and memory impairment (1 patient each) were deemed possibly related to treatment; eye pain, headache, buttock pain, ALT, chest wall pain, bilirubin, renal failure, AST, platelet count decreased, dyspnea, fever, insomnia, catheter infection (1 patient each), and headache, creatinine increased (2 patients each) were deemed unlikely or not related to study treatment. See table 1 below for summary of adverse events regardless of attribution. References: Tan WW, Dueck AC, Flynn P, Steen P, Anderson D, Rowland K, Nothfeldt D, Lingle W, Copland J, Perez EA. N0539 phase II trial of fulvstrant and bevacizumab in patients with metastatic breast cancer previously treated with an aromatase inhibitor: a North Central Cancer Treatment Group trial. San Antonio Breast Cancer Symposium 2009, abstract #4096. Abstract: Background: Treatment of aromatase refractory metastatic breast cancer (MBC) is difficult and challenging. Estrogen receptor (ER) resistance causes enhanced expression of the vascular endothelial growth factor (VEGF). Several studies have shown that the ER interacts with the VEGF pathway and is an important mechanism of resistance. Therefore we embarked on a phase II study of fulvestrant, a complete ER suppressor and bevacizumab, a well studied VEGF monoclonal antibody in aromatase refractory MBC patients. Methods: A single stage phase II study with an interim analysis of fulvestrant and bevacizumab was conducted with these objectives: 6 month progression-free survival rate (PFS), tumor response, toxicity, and overall survival. Regimen: fulvestrant 250 mg day 1 and 15 (cycle 1) then day 1 (cycle 2 and beyond) and bevacizumab 10 mg/kg days 1 and 15 of each 4 weeks is a cycle. Results: At the time of interim analysis, 11/20 evaluable patients achieved 3-month progression-free survival status while remaining on treatment for at least 3 months, not meeting the protocol specified efficacy requirements and thus halting accrual. 36 patients were enrolled from September 2007-December 2008; 33 patients were evaluable. Number of prior metastatic chemotherapy regimens: 0 in 26 patients and 1 in 7 patients. 22 (67%) patients received prior

16 hormonal therapy in the metastatic setting. 18 (55%) had measurable disease. A median of 6 cycles (range 1-19) were administered. 12/33 evaluable patients (95% CI:20-55%) achieved 6-month progression-free survival status while remaining on treatment for a least 6 months. Among 18 patients with measurable disease, 2 (11%) patients (CI:1.4-35%) had a confirmed tumor response (both PR). Additionally, 2 patients had stable disease for greater than 6 months, for a clinical benefit rate of 22%. Median follow up was 8.5 months (range months). Median progression-free survival was 6.2 months (95% CI: months). The 6 -month overall survival rate was 84.8% (95% CI: %). The median dose level administered was 250 mg for fulvestrant and 10 mg/kg for bevacizumab for cycles The most common grade 3/4 adverse events (AEs) were hypertension 2 (6%), headache pain 2 (6%), and confusion 2 (6%). There was 1 grade 5 central nervous system hemorrhage. 13 (39%) patients experienced a grade 3 non-hematologic AE and 4 (12%) experience a grade 4+ non-hematologic AE. Conclusion: Fulvestrant/ bevacizumab is safe and tolerable. Although this regimen did not meet its statistical endpoint, 22% of evaluable patients with aromatase refractory diesease achieved clinical benefit with minimal toxicity. Table 1: Adverse Event Summary Protocol N05C3 - Peripher Neuro/Vit E Adverse Events(Regardless of Attribution) Arm A Evaluable Patients: 33 N % Patients with at least one: Arm Grade 3+ Adverse Event A Grade 4+ Adverse Event A Grade 3+ Hem Adverse Event A Grade 3+ Non-Hem Adverse Event A Grade 4+ Non-Hem Adverse Event A

17 Protocol N05C3 - Peripher Neuro/Vit E Adverse Events For All Patients(Regardless of Attribution) Arm A Evaluable Patients: 33 Grade Adverse Event N % N % N % N % N % Type Arm DIARRHEA A NAUSEA A ALKALINE PHOSPHATASE INCREASED A HYPERTENSION A PROTEINURIA A RASH A HEADACHE A FATIGUE A MUCOSITIS ORAL A EPISTAXIS A VOMITING A ARTHRALGIA A BILIRUBIN A CONFUSION A DYSPNEA A UPPER GASTROINTESTINAL HEMORRHAG A BONE PAIN A CATHETER INFECTN A CREATININE INCREASED A DEHYDRATION A HOT FLASHES A LOWER GASTROINTESTINAL HEMORRHAG A NEURO A THROMBOSIS A ACTVTD PRTL THROMBOPLASTIN TM PR A ALANINE AMINOTRANSFERASE INCREAS A ALLERGIC RHINITIS A ANEMIA A ANOREXIA A 1 3.0

18 Grade Adverse Event N % N % N % N % N % ASPARTATE AMINOTRANSFERASE INCRE A BUTTOCK PAIN A CHEST WALL PAIN A CONSTIPATION A DERMATOLOGY A DISSEMINATED INTRAVASCULAR COAGU A DIZZINESS A ENCEPHALOPATHY A EYE PAIN A FEVER A HYPERGLYCEMIA A INSOMNIA A INTRACRANIAL HEMORRHAGE A ISCHEMIA CEREBROVASCULAR A L VENTRICULAR FAIL A MEMORY IMPAIRMENT A MYALGIA A PHARYNGEAL MUCOSITIS A PLATELET COUNT DECREASED A RENAL FAILURE A SKIN INFECTION A URNRY TRCT INFECTN A VAGINAL HEMORRHAGE A WEIGHT GAIN A WEIGHT LOSS A 1 3.0

19 NCCTG Status Report for Study N May 2011 Randomized Phase II Trial of Capecitabine and Lapatinib with or without IMC- A12 in Patients with HER2 Positive Breast Cancer Previously Treated with Trastuzumab and an Anthracycline and/or a Taxane Purpose of Study: 1) To compare progression-free survival of HER2+ breast cancer patients randomized to receive lapatinib and capectitabine +/- IMC-A12. 2) To assess the safety and tolerability of lapatinib and capecitabine +/- IMC-A12 in HER2+ breast cancer patients. 3) To compare the overall survival time, time to treatment failure, confirmed tumor response rate, and duration of response of lapatinib and capecitabine +/- IMC-A12 in HER2+ breast cancer patients. 4) To assess patient compliance per treatment arm and to compare overall quality of life and treatment side effects via patient-reported outcomes between treatment arms. Design Schema: Study Chair: Statistician: COHORT 1: Safety Analysis (first 10 patients only) Capecitabine, Lapatinib, IMC-A12 COHORT 2: Randomized Treatment Capecitabine, Lapatinib, +/- IMC-A12 Paul Haluska Jr, M.D. Ph.D. Albert G. Bernath Jr, M.D. (NCCTG) Amylou C. Dueck, Ph.D. Projected Number of Patients: 154 Treating Agent Dose Level Route Day ReRx Schedule: Cohort 1 Arm B IMC-A12 6 mg/kg IV 1, 8, 15 q21 days lapatinib 1250 mg 1X daily PO continuously q21 days capecitabine 1000 mg/m 2 2X daily PO 1-14 q21 days Cohort 2 Arm A lapatinib 1250 mg 1X daily PO continuously q21 days Arm A capecitabine 1000 mg/m 2 2X daily PO 1-14 q21 days Arm B IMC-A12 6 mg/kg IV 1, 8, 15 q21 days Arm B lapatinib 1000 mg 1X daily PO continuously q21 days Arm B capecitabine 825 mg/m 2 2X daily PO 1-14 q21 days

20 Study Design: This is a randomized phase II screening design preceded by a safety cohort of 10 patients (pts). The study will temporarily close after the first 10 pts are registered. Following the initial safety cohort, the two arm randomized trial will use a dynamic allocation procedure to allocate patients in a 2:1 ratio to capecitabine and lapatinib with IMC-A12 or capectiabine and lapatinib, respectively. The primary endpoint of this trial is progression-free survival (PFS). PFS is defined as the time from randomization to the earliest date of documentation of disease progression. Analysis of the primary endpoint will be performed using Cox regression with treatment group as a single covariate. The distribution of PFS time will be estimated by the Kaplan-Meier method for each treatment group. Median PFS will be estimated using Kaplan-Meier estimates with 95% confidence intervals. The comparison of the treatment regimen of capecitabine and lapatinib with IMC-A12 to the treatment of capecitabine and lapatinib will be performed using a 1-sided α = 0.10 log rank test. The first 10 pts on this study will receive capecitabine and lapatinib with IMC-A12. After these pts have been treated for a least one cycle, cycle one adverse event data for all available pts (at least 6) will be reviewed for the adverse event stopping rule. These first 10 pts will not be included in the randomized comparison of efficacy endpoint between the two arms but will be included in the computation of the final adverse event rates of capecitabine and lapatinib with IMC-A12. Following the accrual of the safety cohort of 10 pts, there will be 132 evaluable pts accrued to the randomized portion of this study. A sample size of 132 eligible pts will yield 90% power to detect a 44% decrease in the risk of a PFS event using a one-sided α = 0.10 log rank test. This result is equivalent to a 15% increase in the 6-month PFS from 60% to 75% or a hazard ratio of Study Status/ Accrual: This study opened on July 20, 2008 and has accrued 38 of the targeted 154 patients as of March 24, Adverse Event Summary: On July 29, 2009 data from the first 8 evaluable patients in the safety cohort were reviewed by the study team (including CTEP, Imclone, and GSK representatives). At that time, overall 50% of the evaluable patients had experienced a grade 3 non-hematologic adverse event. The most common grade 3 events experienced included diarrhea (3, 38%), fatigue (2, 25%), and oral cavity mucositis (2, 25% each functional/symptomatic and clinical exam). Also at that time, 6 of 7 evaluable patients with Cycle 2 data available required dose reduction of capecitabine in Cycle 2 (due to diarrhea for 3 patients, mucositis for 1 patient, hand-foot syndrome for 1 patient, and other non-hematologic AE for 1 patient); and 5 of 7 evaluable patients with Cycle 2 data available required a dose reduction of lapatinib in Cycle 2 or 3 (due to diarrhea for 4 patients and non-protocol specified reason for 1 patient). This prompted an amendment to reopen to the randomized portion of the

21 study with a reduced dose of capecitabine and lapatinib when given with IMC-A12 (capecitabine and lapatinib doses remain unchanged on the control arm). Regular adverse event monitoring continues via the adverse event stopping rule. Adverse event information is available for 8 Arm A patients and 20 Arm B patients from the Safety and Randomized cohorts combined. Overall, 13/28 (46%) has experienced a Grade 3 non-hematologic event and 1 (4%) has received a Grade 4 non-hematologic event. Four (50%) of the Arm A patients experienced a Grade 3 non-hematologic adverse event and no patients on Arm A experienced a Grade 4 adverse event. The Grade 3 adverse events include diarrhea (2), skin infection (1), urinary tract infection (1), fatigue (1), peripheral motor neuropathy (1), seizure (1), neutropenia (1), and vomiting (1). All except the seizure and vomiting were thought to be at least possibly related to treatment. Nine (45%) of the Arm B patients experienced a Grade 3 non-hematologic or higher adverse event and 1 (5%) of these was a Grade 4 non-hematologic adverse event. The Grade 4 adverse event is thrombosis (thought unlikely to be related to study treatment) and the Grade 3 adverse events include diarrhea (4), fatigue (2), oral cavity mucositis [functional/symptomatic] (2), oral cavity mucositis [clinical exam] (2), pharyngeal mucositis (2), hand/foot skin reaction (2), dehydration (1), hypocalcemia (1), hypotension (1), anorexia (1), hypokalemia (1), and cholecystitis (1). All of the Grade 3 adverse events are thought to be at least possibly related to treatment except for the dehydration, hypotension, nausea, and cholecystitis. The cardiac and Grade 4 adverse event rate stopping rule boundaries have not been crossed.

22 Table 1: Adverse Event Summary Adverse Events(Regardless of Attribution) Reported as of March 24, 2011 Arm A Evaluable Patients: 8 Arm B Evaluable Patients: 20 N % Patients with at least one: Arm Grade 3+ Adverse Event A B Grade 4+ Adverse Event B Grade 3+ Hem Adverse Event A Grade 3+ Non-Hem Adverse Event A B Grade 4+ Non-Hem Adverse Event B Adverse Event Type DIARRHEA FATIGUE SKIN RXN-HAND/FOOT HYPERGLYCEMIA ORAL CAV MS CE ANEMIA MUCOSITIS ORAL Grade N % N % N % N % Arm A B A B A B A B A B A B A B

23 Grade Adverse Event N % N % N % N % NAUSEA A B ASPARTATE AMINOTRANSFERASE INCRE A B RASH A B ALANINE AMINOTRANSFERASE INCREAS A B DRY SKIN A B NEUTROPHIL COUNT DECREASED A B ANOREXIA B TASTE B CONSTIPATION B HYPOKALEMIA B LEUKOPENIA A B NAIL CHANGES B PERIPHERAL SENSORY NEUROPATHY A B PHARYNGEAL MUCOSITIS B PHARYNX MS CE B PLATELET COUNT DECREASED A B PRURITUS A B ALKALINE PHOSPHATASE INCREASED B AMYLASE B

24 Grade Adverse Event N % N % N % N % BILIRUBIN A B CREATININE INCREASED B DYSPNEA B EPISTAXIS B HYPOMAGNESEMIA B VISION-BLURRED B VOMITING A B WEIGHT LOSS B CHEST WALL PAIN B DEHYDRATION B DYSPHAGIA B GLUCOSE INTOLERANCE B HYPERCHOLESTEROLEMIA B HYPOALBUMINEMIA A B INSOMNIA B L VENTRICULAR FAIL A B LIPASE INCREASED B MYALGIA B PERIPHERAL MOTOR NEUROPATHY A SEIZURE A B VISION-PHOTOPSIA B ALLERGIC RHINITIS B ANXIETY B BACK PAIN B 1 5.0

25 Grade Adverse Event N % N % N % N % BONE PAIN A BREAST PAIN B BRUISING B CELLULITES INFECTN B CHOLECYSTITIS B CONFUSION B COUGH B DIZZINESS B DRY EYE B DRY MOUTH B DYSPEPSIA B HEADACHE B HYPERSENSITIVITY A HYPERTRIGLYCERIDEMIA B HYPOCALCEMIA B HYPONATREMIA B HYPOPHOSPHATEMIA B HYPOTENSION B LYMPHOCYTE COUNT DECREASED B NECK PAIN B PAIN B PAIN IN EXTREMITY B PALPITATIONS B PHARYNGOLARYNGEAL PAIN B PNEUMONITIS B PROTEINURIA B RECTUM MS CE B SKIN INFECTN A STOMACH PAIN B 1 5.0

26 Grade Adverse Event N % N % N % N % THROMBOSIS B URINARY TRACT INFECTION B URNRY TRCT INFECTN A URTICARIA A

27 NCCTG Status Report for Study N0735 May 2011 Phase II Trial of Albumin-Bound Paclitaxel in Combination with Gemcitabine and Bevacizumab in Patients with Metastatic Breast Cancer Purpose of Study: Schema: 1. To evaluate the 6-month progression-free survival rate of albuminbound paclitaxel + gemcitabine + bevacizumab in patients with metastatic breast cancer. 2. To describe the adverse event profile of albumin-bound paclitaxel + gemcitabine + bevacizumab (adverse events graded using the NCI CTCAE version 3.0). 3. To describe the progression-free survival, overall survival, confirmed response rate, duration of response, and time to treatment failure of patients receiving albumin-bound paclitaxel + gemcitabine + bevacizumab. 4. To describe the QOL of patients receiving albumin-bound paclitaxel + gemcitabine + bevacizumab. Registration Treatment (albumin-bound paclitaxel+gemcitabine+bevacizumab) Progression, Adverse Events, Patient Refusal Event Monitoring Study Chair: Statistician: Donald W. Northfelt, M.D. Phillip J. Stella, M.D. Amylou C. Dueck, Ph.D. Projected Number of Patients: 51 Treating Schedule: Agent Sequence Dose Level Route Day ReRx Albumin-bound paclitaxel First 125 mg/m 2 IV (30 min) 1 and 8 q21 days Gemcitabine Second 1000 mg/m 2 IV (30 min) 1 and 8 q21 days Bevacizumab Third 15 mg/kg IV (90 min) 1 q21 days Study Design: This protocol will assess the efficacy of albumin-bound paclitaxel + gemcitabine + bevacizumab in patients with metastatic breast cancer using a one-stage phase II study design. The primary endpoint of this trial is the 6- month progression-free survival rate. A patient is considered a success if the

28 patient is 6 months from registration without a documentation of disease progression (note, the patient need not be on study treatment at 6 months to be considered a success). The largest success proportion where the proposed treatment regimen would be considered ineffective in this population is 60%, and the smallest success proportion that would warrant subsequent studies with the proposed regimen in this patient population is 77.5%. The following one-stage design based on properties of the binomial distribution uses 47 patients to test the null hypothesis that the true success proportion in a given patient population is at most 60%. (The null 6-month progression-free survival rate of 60% is based on the Kaplan-Meier estimate of 6-month progression-free survival from N0531 as reported at ASCO 2007.) Enter 47 patients into the study. If 32 or fewer successes are observed in the first 47 evaluable patients, we may consider this regimen ineffective in this patient population. If 33 or more successes are observed in the first 47 evaluable patients, we may recommend further testing of this regimen in subsequent studies in this population. Study Status/ Accrual: Adverse Events: References: This study was opened on 11/07/2008 and was closed on 03/29/2010 with a final accrual of 50 patients. There was 1 patient cancellation during the course of the study. Adverse Event (AE) information is available on 98% (49/50) patients. There were no grade 5 events reported. There were 3 grade 4 non-hematologic adverse events (lipase increased, renal failure, and thrombosis) seen in 3 patients that were deemed possibly related to the study medication. There were four grade 4 non-hematologic adverse events (fatigue, constipation, back pain, and thrombosis) seen in three patients that were deemed not related or unlikely related to the study medication. Northfelt DW, Dueck AC, Flynn TP, Zander PJ, Stella PJ, Melnik M, Pavey ES, Perez EA. Phase II trial combining nab-paclitaxel (NP), gemcitabine (G), and bevacizumab (B) in patients (pts) with metastatic breast cancer (MBC): NCCTG N0735. American Society of Clinical Oncology 2011 Annual Meeting, abstract #1126.

29 Table 1: Adverse Event Summary Protocol N MBC ABI007 GEMZAR AVASTN Adverse Events(Regardless of Attribution) Reported as of March 24, 2011 Arm A Evaluable Patients: 49 N % Patients with at least one: Arm Grade 3+ Adverse Event A Grade 4+ Adverse Event A Grade 3+ Hem Adverse Event A Grade 4+ Hem Adverse Event A Grade 3+ Non-Hem Adverse Event A Grade 4+ Non-Hem Adverse Event A Grade Adverse Event N % N % N % N % Type Arm FATIGUE A ALOPECIA A ANEMIA A NEUTROPHIL COUNT DECREASED A NAUSEA A MYALGIA A PERIPHERAL SENSORY NEUROPATHY A ARTHRALGIA A MUCOSITIS ORAL A PLATELET COUNT DECREASED A EPISTAXIS A DYSPNEA A DIARRHEA A VOMITING A FEVER A PROTEINURIA A LEUKOPENIA A

30 Grade Adverse Event N % N % N % N % SKIN RXN-HAND/FOOT A CONSTIPATION A HYPERTENSION A PHARYNGEAL MUCOSITIS A ANOREXIA A ALANINE AMINOTRANSFERASE INCREAS A THROMBOSIS A ASPARTATE AMINOTRANSFERASE INCRE A CREATININE INCREASED A DEHYDRATION A EDEMA LIMBS A HEADACHE A HYPERSENSITIVITY A ABDOMINAL PAIN A BLADDER INFECTN A FEBRILE NEUTROPENIA A HYPOCALCEMIA A HYPOKALEMIA A LOWER GASTROINTESTINAL HEMORRHAG A MUSCLE WEAKNESS LOWER LIMB A RASH A RESP TRACT HEMORR A RESP TRACT INFECTN A VISION-BLURRED A ATRIAL FLUTTER A BILIRUBIN A BONE PAIN A CATHETER INFECTN A DRY SKIN A HOT FLASHES A LYMPHOCYTE COUNT DECREASED A NAIL CHANGES A PERIPHERAL MOTOR NEUROPATHY A 2 4.1

31 Grade Adverse Event N % N % N % N % PRURITUS A PULMONARY A RENAL FAILURE A SKIN HYPERPIGMENTATION A UPPER GASTROINTESTINAL HEMORRHAG A URINARY TRACT INFECTION A WEIGHT LOSS A WOUND DEHISCENCE A ALKALINE PHOSPHATASE INCREASED A AMYLASE A ATRIAL FIBRILLATION A BACK PAIN A BRONCHOPULMONARY HEMORRHAGE A CD4 LYMPHOCYTES DECREASED A COUGH A DIZZINESS A DYSPEPSIA A GALLBLADDER OBSTRUCTION A GGT A HYPERGLYCEMIA A HYPONATREMIA A HYPOTENSION A HYPOXIA A INFECTION-NO ANC A INJECTION SITE REACTION A ISCHEMIA/INFARCTION A LIPASE INCREASED A MUSCLE WEAKNESS A NECK INFECTN A ORAL CAVITY FISTULA A ORAL PAIN A PAIN-CHEST A PLEURAL EFFUSION A 1 2.0

32 Grade Adverse Event N % N % N % N % PNEUMONIA GR 0-2 ANC A PNEUMONIA GR 3-4 ANC A PNEUMONITIS A PNEUMOTHORAX A PULMONARY HEMORR A RASH ACNEIFORM A SINUSITISN A SKIN INFECTN A SKIN ULCERATION A SYNCOPE A TASTE A TOOTH INFECTN A UPPER RESPIRATORY INFECTION A UPR AIRWAY INFECTN A VAGINAL DRYNESS A VISION A 1 2.0

33 NCCTG Status Report for Study N0937 May 2011 Phase II Trial of Brostallicin and Cisplatin in Patients with Metastatic Triple Negative Breast Cancer Purpose of Study: Schema: Study Chair: Statistician: 1. To identify any clinical efficacy of brostallicin and ciplatin in the treatment of breast cancer patients having a triple negative ER/PR/HER2 negative) phenotype, as measured by progression-free survival (PFS) at 3 months. 2. To describe the confirmed tumor response rate of patients with measurable disease receiving brostallicin and cisplatin. 3. To describe the duration of response in patients with measurable disease receiving brostallicin and cisplatin. 4. To describe the 6-month progression-free survival of patients receiving brostallicin and cisplatin. This endpoint will be especially relevant if a high proportion of 1 st and 2 nd line metastatic patients are enrolled. 5. To describe the overall survival (OS) of patients receiving brostallicin and cisplatin. 6. To evaluate the adverse event profile of the study regimen (adverse events graded using the CTEP Active Version of the CTCAE) 7. To assess baseline GSH levels in whole blood (level prior to the administration of cisplatin) of patients with triple negative MBC and to correlate those levels with the primary and secondary endpoints. 8. To evaluate whether cisplatin administered the day prior (minus hours) tothe administration of brostallicin leads to an increased level of glutathione/glutathione S-transferase levels in vivo and whether such increase is associated with improvement of the primary and secondary endpoints. 9. To assess the prevalence of BCRA-1 mutation by IHC on the primary or metastatic tumor in patients with triple negative MBC. 10. To assess the association of BCRA-1 mutation by IHC with the primary and secondary endpoints. 11. As part of ongoing research for NCCTG breast studies, we are banking paraffin embedded tissue blocks/slides and blood products for future studies. Registration Cisplatin + Brostallicin Alvaro Moreno-Aspitia, M.D. Kendrith M Rowland Jr, M.D. Heshan Liu, M.S.

34 Projected Number of Patients: 46 Treating Schedule: Agent Dose Route Days ReRx Cisplatin 50 mg/m2 IV 1 Every 3 weeks Brostallicin 10 mg/m2 IV 2 Every 3 weeks Study Design: A single-stage phase II study design will be used to assess the efficacy of brostallicin and cisplatin in patients with metastatic triple negative breast cancer. The study was designed to test whether the 3-month progression-free survival (PFS) rate is at most 35% against the alternative that the PFS rate is at least 55%. Forty-two evaluable patients will be enrolled into this study. If 18 or fewer 3- month progression-free survivors are observed in these 42 evaluable patients, we will conclude that this treatment is insufficiently active in this population. If 19 or more 3-month progression-free survivors are observed in all 42 evaluable patients, this result will be considered adequate evidence of efficacy and this treatment may be recommended for further testing. This design has a significance level of 0.10 and a statistical power of at least 89% to detect a confirmed response rate of at least 55%. Study Status/ Accrual: This study opened on 06/25/2010 and has accrued 21 of a targeted 46 patients as of 03/24/2011 The study will be temporarily closed on February 11, 2011 for further safety analysis and interim analysis of endpoint. No patients have been deemed ineligible and 10 patients are still receiving treatment. Adverse Events: Adverse Event (AE) information is available on 90% (19/21) patients. One patient suffered a grade 4 non-hemetological event (hypokalemia) which was deemed unlikely related to the study medication. Three patients suffered grade 3 febrile neutropenia all deemed related to the study medication. No grade 5 adverse events were reported.

35 Table 1: Adverse Event Summary Protocol N Breast Brostallicin Cisplatin Adverse Events(Regardless of Attribution) Reported as of March 24, 2011 Arm A Evaluable Patients: 19 N % Patients with at least one: Arm Grade 3+ Adverse Event A Grade 4+ Adverse Event A Grade 3+ Hem Adverse Event A Grade 4+ Hem Adverse Event A Grade 3+ Non-Hem Adverse Event A Grade 4+ Non-Hem Adverse Event A Grade Adverse Event N % N % N % N % Type Arm FATIGUE A PLATELET COUNT DECREASED A NEUTROPHIL COUNT DECREASED A ANEMIA A NAUSEA A ALKALINE PHOSPHATASE INCREASED A ALOPECIA A PERIPHERAL SENSORY NEUROPATHY A VOMITING A ALANINE AMINOTRANSFERASE INCREAS A DIARRHEA A FEBRILE NEUTROPENIA A WHITE BLOOD CELL DECREASED A ANOREXIA A BONE PAIN A CONSTIPATION A DYSPNEA A HYPOCALCEMIA A

36 Grade Adverse Event N % N % N % N % HYPOKALEMIA A MUCOSITIS ORAL A PAIN IN EXTREMITY A PHARYNGEAL MUCOSITIS A ABDOMINAL PAIN A ANXIETY A ASPARTATE AMINOTRANSFERASE INCRE A BREAST PAIN A CHEST WALL PAIN A CREATININE INCREASED A DEHYDRATION A DYSGEUSIA A EPISTAXIS A FEVER A HEADACHE A HYPOALBUMINEMIA A HYPOMAGNESEMIA A HYPONATREMIA A LUNG INFECTION A LYMPHEDEMA A LYMPHOCYTE COUNT DECREASED A MALAISE A MYALGIA A PERIPHERAL MOTOR NEUROPATHY A PLEURAL EFFUSION A SKIN INFECTION A SYNCOPE A 1 5.3