NSABP: FB-11. Shannon Puhalla, MD

Transcription

1 NSABP: FB-11 Phase II Randomized Study Evaluating the Biological and Clinical Effects of the Combination of Palbociclib with Letrozole as Neoadjuvant Therapy in Post- Menopausal Women with Estrogen Receptor Positive Primary Breast Cancer Shannon Puhalla, MD

2 CDK 4/6 regulates G1 S cell cycle progression CDK 4 and CDK 6 act to phosphorylate Rb with cyclin D1 which drives cell cycle progression CDK 4/6 inhibitors block Rb phosphorylation and in turn block tumor cell progression CDK 4/6 Inhibitors

3 CDK 4/6 Inhibitors have preferential activity in ER+ cancer Preclinical studies have identified an association between sensitivity to CDK 4/6 inhibitors and the luminal ER subtype There is elevated expression of cyclin D1 and Rb and reduced p16 expression in luminal cancers 1 Synergistic activity between tamoxifen and PD (palbociclib) 2 1 Breast Cancer Res 2009;11(5):R77; 2 Nat Rev Can 2011;11:558

4 Palbociclib Palbociclib is an orally active potent and highly selective reversible inhibitor of CDK4 and CDK6 Prevents cellular DNA synthesis by prohibiting progression of the cell cycle from G1 into the S phase. Appears to act primarily as an anti-proliferative agent although there are some data that indicate this may be accompanied by a pro-apoptotic effect.

5 PALOMA-1 Study Part 1 (n = 66) Eligibility Postmenopausal ER+/HER2- BC Eligibility Part 2 (n = 99) Postmenopausal ER+/HER2- BC CCND1 amplification and/or p16 loss by FISH R R 1:1 1:1 PD LET LET PD LET LET Finn RS et al. Proc SABCS 2012, AACR 2014.

6 AACR 2014

7 Best Overall Response: Patients with Measurable Disease Response rate PD LET LET Objective response (n = 64, 65) Complete response Partial response Clinical benefit rate (n = 84, 81) 45% 31% 0% 0% 45% 31% 70% 44% Finn RS et al. Proc SABCS 2012;Abstract S1-6.

8 Select Treatment-Related Adverse Events (AEs) Grade 3/4 AEs ( 10%) PD LET (n = 83) LET (n = 77) Neutropenia 61.4% 1.3% Leukopenia 16.9% 0% Anemia 6% 1.3% Fatigue 4.8% 1.3% Thrombocytopenia 1.2% 0% 13% of pts in palbo/let arm discontinued treatment compared to 2% with let alone Finn RS et al. SABCS 2012, AACR 2014

9 New Data from PALOMA-3 Palbociclib with fulvestrant vs. fulvestrant alone Endocrine resistant, progression on prior AI or tamoxifen Pre-meno on ovarian ablation or post-menopausal Results: median PFS was 9.2 months for Palbo+F and 3.8 months for PLB+F (HR 0.422, 95% CI to 0.560, P< ). Adverse effects: neutropenia (78.8% combo vs. 3.5% fulv alone), leucopenia (45.5% vs. 4.1%), and fatigue (38.0% vs. 26.7%). Low rates of febrile neutropenia on both arms (0.6%)

10 NSABP: FB-11 ( PALLET) NSABP Chair: Norman Wolmark, MD Protocol Chair: Shannon Puhalla, MD Protocol Officer: Samuel Jacobs, MD Protocol Statistician: Marc Buyse, ScD In collaboration with Institute of Cancer Research and the Royal Marsden NHS Foundation Trust UK Protocol Chair: Stephen Johnston, MD Translational Research Chair: Mitch Dowsett, PhD Lead Statistician: James Morden

11 Postmenopausal women with estrogen receptor positive, HER2- negative, invasive breast cancer suitable for neoadjuvant therapy with letrozole Stratification by Country (UK; USA/CAN) N=306 3:2:2:2 RANDOMIZATION ARM A ARM B ARM C ARM D Letrozole alone for 14 weeks Letrozole alone For 2 weeks followed by Palbociclib alone For 2 weeks followed by Letrozole + Palcociclib for 14 weeks Letrozole + Palbociclib For 12 weeks SURGERY

12 Primary aims Aim: To compare the changes in the proliferation marker Ki67 (% positive tumor cells) as tested by immunohistochemistry (IHC) from baseline and following 14 weeks of treatment with letrozole with or without palbociclib -Endpoint: Ki67 changes as tested by IHC Aim: To determine the clinical response by ultrasound after 14 weeks of therapy with letrozole with or without palbociclib -Endpoint: Clinical response of breast and axillary lesions as measured by ultrasound after 14 weeks of study therapy

13 Secondary Aims Pathological complete response (pcr) Preoperative endocrine prognostic index (PEPI) PEPI score after letrozole with or without 14 weeks of palbociclib Toxicity Correlative science

14 Key Eligibility Operable ER-positive/HER2-negative, invasive early breast cancer, suitable for neoadjuvant AI treatment Breast tumor with an ultrasound size of at least 2 cm Patients must be postmenopausal ECOG 0 or 1; able to swallow oral medication

15 Key Ineligibility Pre or Peri-menopausal women Inflammatory or inoperable breast cancer HER2-positive as per ASCO-CAP guidelines Prior endocrine therapy for breast cancer or any other treatment administered for the currently diagnosed breast cancer Concurrent use of hormone replacement therapy or any other estrogen containing medication (use within 4 weeks of baseline tissue sample collection)

16 FB-11 Therapy Core Core (prior to beginning Week 3 study therapy) Core Groups A B Weeks Between Surgery Surgery C Surgery D Surgery Letrozole Palbociclib

17 FB-11 Therapy Letrozole is administered orally as a 2.5 mg daily tablet Palbociclib is administered orally as a 125 mg capsule 3 weeks on, 1 week off Taken with food At the same time each day Use of diary, calendar, or other tool to record doses is strongly encouraged

18 FB-11 Therapy Patients on Arms B, C, and D will remain on palbociclib up to Week 14 (or if there has been delay in treatment, until they have completed 14 days of palbociclib in the final treatment cycle). The end of study therapy for patients in Arm A will be at the completion of week 14.

19 FB-11 Therapy All patients should continue letrozole until surgery. Letrozole will not be considered study therapy given after week 14 or end of the final treatment cycle. Surgery will be scheduled for weeks post randomization. Surgery will be considered the end of trial treatment for all treatment groups. Letrozole may continue beyond surgery in all groups as per treating physician's choice but will no longer be considered study therapy after surgery.

20 Assessment of Effect Tumor response will be evaluated by physical exam and ultrasound by ECOG Response criteria At baseline and at week 14 Lesions will be classified as measurable (target) or non-measurable (non-target) Tumor assessment by physical exam will also be performed at weeks 2, 4, 6, 8 and 10 during therapy pcr will be performed by the local pathologist at the time of surgery Follow-up visit at 12 months following randomization

21 Correlative Science Mandatory core biopsy tumor samples will be collected: prior to study entry during week 2 of therapy at week 14 of study therapy on all patients On the same day as the core biopsy procedure, blood samples will be collected Optional core biopsy and blood specimens will be requested if a patient stops study therapy prior to completion and will be collected on consenting patients within The final biopsy should be collected within 48 hours from the last dose of study therapy

22 Amendment #1 The following collection and submission of additional breast tumor samples will be a study requirement. If any tumor a centimeter in size (about one half of an inch) or larger is found during surgery, a small sample of this tumor will be sent to NSABP Division of Pathology for the research purposes related to FB-11.

23 Amendment #2 Comparison of surgical intent (mastectomy; breast conservation) Aim: To compare changes between surgical intent at baseline; surgical intent after 14 weeks; and actual surgery received after treatment with letrozole with or without palbociclib. Endpoint: Actual surgery received after treatment.

24 Questions If a patient had CBC/platelet count prior to study entry does it need to be repeated? What day does weekly CBC/platelet count need to be done? What happens if CR on week 14 re: bx?

25 Groups A FB-11 TREATMENT SCHEDULE WEEKS Cycle 1 Cycle 2 Cycle 3 Cycle 4 L L L L L L L L L L L L L L Weeks Surgery B L L L L L L L L L L L L L L P P P P P P P P P Surgery C L L L L L L L L L L L L P P P P P P P P P P P Surgery D Sample Collections * Letrozole Palbociclib L L L L L L L L L L L L L L P P P P P P P P P P P Surgery * * * All Patients should continue letrozole until surgery (however, it is not considered study therapy after week 14) L P * Baseline, Week 2, Week 14, and Surgery Sample Collections Week 2 samples are collected before beginning week 3 study therapy Week 14 samples are collected within 48 hours after the last dose of study therapy Tumor sample is required if gross residual disease 1cm remains at definitive surgery

26 Groups A FB-11 TREATMENT SCHEDULE WEEKS Cycle 1 Cycle 2 Cycle 3 Cycle 4 L L L L L L L L L L L L L L Weeks Surgery Sample Collections * Letrozole Palbociclib * * * All Patients should continue letrozole until surgery (however, it is not considered study therapy after week 14) L P * Baseline, Week 2, Week 14, and Surgery Sample Collections Week 2 samples are collected before beginning week 3 study therapy Week 14 samples are collected within 48 hours after the last dose of study therapy Tumor sample is required if gross residual disease 1cm remains at definitive surgery

27 Groups FB-11 TREATMENT SCHEDULE WEEKS Cycle 1 Cycle 2 Cycle 3 Cycle 4 Weeks B L L L L L L L L L L L L L L P P P P P P P P P Surgery Sample Collections * Letrozole Palbociclib * * * All Patients should continue letrozole until surgery (however, it is not considered study therapy after week 14) L P * Baseline, Week 2, Week 14, and Surgery Sample Collections Week 2 samples are collected before beginning week 3 study therapy Week 14 samples are collected within 48 hours after the last dose of study therapy Tumor sample is required if gross residual disease 1cm remains at definitive surgery

28 Groups FB-11 TREATMENT SCHEDULE WEEKS Cycle 1 Cycle 2 Cycle 3 Cycle 4 Weeks C L L L L L L L L L L L L P P P P P P P P P P P Surgery Sample Collections * Letrozole Palbociclib * * * All Patients should continue letrozole until surgery (however, it is not considered study therapy after week 14) L P * Baseline, Week 2, Week 14, and Surgery Sample Collections Week 2 samples are collected before beginning week 3 study therapy Week 14 samples are collected within 48 hours after the last dose of study therapy Tumor sample is required if gross residual disease 1cm remains at definitive surgery

29 Groups FB-11 TREATMENT SCHEDULE WEEKS Cycle 1 Cycle 2 Cycle 3 Cycle 4 Weeks D Sample Collections * Letrozole Palbociclib L L L L L L L L L L L L L L P P P P P P P P P P P Surgery * * * All Patients should continue letrozole until surgery (however, it is not considered study therapy after week 14) L P * Baseline, Week 2, Week 14, and Surgery Sample Collections Week 2 samples are collected before beginning week 3 study therapy Week 14 samples are collected within 48 hours after the last dose of study therapy Tumor sample is required if gross residual disease 1cm remains at definitive surgery

30 FB-11 Study Tips Order Specimen Kits as soon as a potential patient has been identified as it usually takes 3-4 business days to arrive. Radiologic tumor measurements must be assessed by ultrasound within 4 weeks prior to study entry. If > than 4 weeks, one option is to obtain ultrasound tumor measurements at the time of the research biopsy.

31 FB-11 Research Sites Date Sites Activated March 2015 Cancer Care Specialists of Illinois May 2015 Long Beach Memorial Medical Center Women & Infants Hospital of Rhode Island June 2015 Allegheny General Hospital VCU Massey Cancer Center Henry Ford Health System Joe Arrington Cancer Research and Treatment Center West Virginia University

32 FB-11 Research Sites July 2015 Providence Oncology and Hematology Clinics August 2015 Metro Minnesota Pending research sites = 9

33 10 9 Enrollment Mar-15 Apr-15 May-15 Jun-15 Jul-15 Aug-15 Sep Mar-15 Apr-15 May-15 Jun-15 Jul-15 Aug-15 Sep-15

34 FB-11 SCREENING AND ENROLLMENT LOG Principal Investigator: NSABP Site Number(s): Site Name(s): Date:(mm/yyyy) Screening Site Patient Initials (L,FM) Screening Date (mm/dd/yyyy) Is Patient Eligible? Date Informed Consent Signed Patient ID Reason for Screen Failure

35 Productivity If a treating site has not enrolled a patient within 4 months after site activation, the site will no longer be considered an active treating site for FB- 11 Call to discuss screening activity

36 FB-11 Is there awareness of FB-11 Trial among surgeons and medical oncologists? Does your site evaluate newly diagnosed breast cancer patients? Is neoadjuvant therapy usually an option for patients with a tumor 2 cm? Does your site participate in tumor board or a multidisciplinary meetings? Are specific clinical trials and potential patients being discussed? How are patients being identified for FB-11 at your site?

37 Thank you