Updates on Use of Radiopharmaceu3cals in Clinical Trials August 22, 2017

Transcription

1 Updates on Use of Radiopharmaceu3cals in Clinical Trials August 22, 2017 Evan Y. Yu, M.D. Professor of Medicine (Oncology) University of Washington Fred Hutchinson Cancer Research Center

2 Discussion Topics Radium-223 background Ongoing clinical trials with Radium-223 therapy Earlier disease states Biomarkers and 8/21/17

3 Radium-223 Mechanism of Ac3on Radium-223 acts as a calcium mimic Naturally targets new bone growth in and around bone metastases Radium-223 is excreted by the small intes@ne Ca Sr Ba Ra

4 Radium-223 Mechanism of Ac3on Range of alpha-particle Radium-223 Bone surface induce double-strand DNA breaks in adjacent tumour cells1 Short of alpha eminers (2-10 cell diameters) = highly localized tumour cell killing and minimal damage to surrounding Perez et al. Principles and Prac.ce of Radia.on Oncology. 5th ed. LippincoN Williams & Wilkins; 2007:103.

5 ALSYMPCA Trial Overall Survival Results HR 0.695; 95% CI, p= % Placebo, n = 268 Median OS: 11.2 months Radium-223, n=541 Median OS: 14.0 months 0 Month Radium Placebo Parker C et al. N Engl J Med 2013;369:

6 ALSYMPCA Overall Survival Stra3fied by Prior Docetaxel Use Prior docetaxel use HR = % CI, 0.565, P = NO prior docetaxel use HR = % CI, 0.562, P = % Radium-223, n = 352 Median: 14.4 months % Radium-223, n = 262 Median: 16.1 months Placebo, n = 174 Median: 11.3 months Placebo, n = 133 Median: 11.5 months 0 Month Radium Placebo Month Radium Placebo Parker GU ASCO 2013

7 ALSYMPCA: Adverse Events of Interest Haematologic Radium-223 (n=509) n (%) All Grades Grades 3 or 4 Placebo (n=253) n (%) Radium-223 (n=509) n (%) Placebo (n=253) n (%) Anemia 136 (27) 69 (27) 54 (11) 29 (12) Neutropenia 20 (4) 2 (1) 9 (2) 2 (1) Thrombocytopenia 42 (8) 14 (6) 22 (4) 4 (2) Non-Haematologic Bone pain 217 (43) 147 (58) 89 (18) 59 (23) Diarrhea 112 (22) 34 (13) 6 (1) 3 (1) Nausea 174 (34) 80 (32) 8 (2) 4 (2) Vomiting 88 (17) 32 (13) 10 (2) 6 (2) Constipation 89 (18) 46 (18) 6 (1) 2 (1) Parker C et al. N Engl J Med 2013;369:

8 ALSYMPCA: Predisposing Factors for Hematologic Toxicity Parameter es3mates for maximum percentage decrease from baseline during on-treatment period in Hb, neutrophils and platelets Baseline variable Parameter Hb (n=870) Neutrophils (n=867) Platelets (n=870) P value Parameter es@mates P value Parameter es@mates P value Study tx (Ra-223/Pbo) < < Current use of bisphosphonates (Y/N) NS NS NS Prior use of Doce (Y/N) NS < EOD 6 mets including superscan (Y/N) Prior EBRT to bone for pain (Y/N) Total ALP ( 220 U//L / < 220 U/L/) NS NS < NS Parker et al., J Clin Oncol 31, 2013 (suppl; abstr 5038)

9 Should Radium-223 be Used Before or Ager Chemotherapy? Only FDA approved for lacking visceral metastasis Stringent eligibility requirements for treatment ANC 1,500/L with subsequent 1,000/L Hb 10 g/dl PLT 100,000/L with subsequent 50,000/L Requires while chemotherapy with docetaxel does not More likely to be able to administer all 6 doses in the pre- vs. post-chemotherapy segng

10 Overall Survival of Radium +/- Abiraterone or Enzalutamide from Early Access Program Post hoc exploratory analysis of the Early Access Program. Abi, abiraterone; Enza, enzalutamide; OS, overall survival Saad F, et al. Lancet Oncol. 2016;17(9): Slide adapted from Neal Shore.

11 ERA 223: Abiraterone +/- Radium-223 for No/ Minimally Symptoma3c bone mcrpc ClinicalTrials.gov NCT Accessed 3/28/2017. Slide adapted from Neal Shore.

12 PEACE-3: Enzalutamide +/- Radium-223 for No/ Minimally Symptoma3c bone mcrpc PI: Silke Gillessen Primary Endpoint: rpfs by PCWG2 ClinicalTrials.gov NCT Accessed 3/28/2017. Slide adapted from Neal Shore.

13 Randomized Phase 2 Trial of Radium-223 for mhspc N = 204 Primary Endpoint: rpfs at landmark Slide adapted from PI: Ajjai Alva NCT

14 Phase 2 study of Sip-T +/- Rad-223 N = 34 Primary Endpoint: PA2024 T cell proliferation Slided adapted from PI: E. Antonarakis NCT Presented by Charles G Drake MD / PhD

15 Study Design & Primary Objec3ves * * * N=45 No limits on number of prior therapies *All are con@nued on GnRH agonist/antagonist **Pembrolizumab 200mg IV q3 wks Stra@fied by high/low volume of bone metastases; alk phos levels Primary Immune objec@ves: cell infiltra@on Characterize into the changes metasta@c in immune bone biopsies cell response from baseline bone and to week blood 8 Secondary objec@ves: safety and tolerability, preliminary efficacy of the combina@on NCT ; Slided adapted from PI: Lauren Harshman

16 DNA Repair Gene Altera3ons are Common in Metasta3c Prostate Cancer 23% of prostate cancers harbor DNA repair The frequency of DNA repair increases with disease progression Robinson D et al. Cell 2015; 161: % of men with metasta@c prostate cancer have a germline altera@on in 16 DNA damage repair genes Age and family history did not affect muta@on frequency Pritchard CC et al. N Engl J Med. July 6,2016.

17 RAPARP Phase 1 Trial Slide adapted from PI: Kelly\Knudsen; Co-PI: Rettig (UCLA), Spondave (UAB); Graff (OHSU), Sartor (Tulane) N=30 NCT

18 PET/CT and Metasta3c Biopsies to Study Mechanisms of Resistance to Radium-223 Eligibility assessment and informed consent Pretreatment biopsy, if appropriate PET1 PIs: Ramos, Yu Begin treatment biopsy, if appropriate PET2 a PET3 Survival monitoring b Metasta@c biopsy, if appropriate and not done arer PET2 a In some cases, PET2 may show progression of disease and in those instances, would represent PET3 in this schema. This scan will occur at 12 weeks ± 2 weeks from ini@a@on of therapy. b Survival monitoring will occur in 3-month intervals. PET: positron-emission tomography

19 DNA Repair Genes and Response to Radium-223 analysis of 49 received radium-223 since May of 49 (53.1%) had a response to radium-223 defined as 30% decline in PSA, 30% decline in alkaline phosphatase or normaliza@on of CTCs 10 of 26 pa@ents previously underwent DNA sequencing 4 of 10 had an altera@on in a DNA repair gene BRCA2, CHEK2, MRE11A, SPOP Prospec@ve trial planned to perform pre-radium-223 metasta@c biopsy and next genera@on sequencing at baseline (UW, Tulane, JH, UCSF, UBC) Determine response in pa@ents with and without DNA repair gene altera@ons

20 177 Lu-DOTAGA PSMA (aka PSMA-I&T) 68 Ga-PSMA 177 Lu-PSMA cycles 68 Ga-PSMA Baum RP et al. J Nucl Med. 2016; 57:

21 177 Lu-PSMA-617 Rahbar K et al. J Nucl Med. 2017; 58:85-90.

22 177Lu-PSMA 225Ac-PSMA Abstract 1431 at SNMMI 2016 annual

23 Take Home Points Radium-223 offers significant survival benefit for with bone mcrpc and symptoms Many trials are ongoing with radium-223 and 2 nd genera@on androgen pathway inhibitors, immuno-oncology agents and now PARP inhibitors Promising trials are underway u@lizing radium-223 in pa@ents in earlier disease states who lack symptoms Both predic@ve and response biomarkers are necessary and are being explored in a limited number of trials There are many promising other radiopharmaceu@cals in development with both beta- (e.g. Lute@um) and alphaeminers (e.g. Ac@nium) tagged to PSMA an@bodies or small molecules

24 Acknowledgements Neal Shore Emmanuel Antonarakis Lauren Harshman Ajjai Alva W. Kevin Kelley Jorge D. Ramos ScoN Tagawa

25 Thank You!