BMT CTN 1702: CTRL-ALT-D

1. BMT CTN 1702: CTRL-ALT-D Clinical Transplant-Related Long-Term Outcomes of Alternative Donor Allogeneic Transplantation

2. Protocol Team William Hogan Mary Horowitz Eric Leifer Brent Logan William Merritt Swati Naik Joseph Pidala Bronwen Shaw Heather Symons Peter Westervelt • Stefan Ciurea • Stephanie Lee • Assad Bashey • Renee Carby • Jason Dehn • Steven Devine • Nancy DiFronzo • NoshaFarhadfar • Iris Gersten • Mike Grunwald • Brandon Hayes-Lattin

3. Background • If there is no matched related donor (MRD), a matched unrelated donor (MUD) has been considered the next best choice • If there is a prolonged search for a MUD, patients may experience disease progression or co-morbidities precluding HCT • Improvements in transplant approaches for alternative donor graft sources (haploidentical, umbilical cord blood, mismatched unrelated donors) demonstrate good outcomes in phase 2 studies • For patients lacking a suitable matched related donor, centers must balance the delay to identify a MUD with the potentially faster availability of alternative graft sources

4. Primary Research Question • Does a search strategy of • (a) a MUD if possible then an alternative donor if a MUD is not available versus • (b) proceeding directly to an alternative donor transplant result in more people getting to transplant and better survival within 2 years after enrollment?

5. Secondary Questions • How long does it take to identify a donor, and what factors are important? • Does a longer time to identify a donor matter for patient outcome? • Why do less than 50% who start a search make it to transplant? • Do outcomes differ depending on the type of donor targeted?

6. Study Design Assumptions • There is equipoise across the field about the best donor but individual centers and physicians have strong preferences • The preferred donor is influenced by center experience, research priorities, and patient-specific factors such as disease, disease status and clinical status • Randomization between different donor sources was not felt to be feasible

7. Very Unlikely group predicts a low rate of MUD HCT: 4% 10/10 in this 2016 paper Same if 8/8

8. Biologic Assignment with ITT No suitable HLA-matched family donor MUD Very Likely (44%) >2 potential MUDs >90% likelihood of MUD MUD Very Unlikely (15%) 0 potentials <10% likelihood of MUD MUD Less Likely (41%) 1-2 potential MUDs 26% likelihood of MUD Usual Center Practice Proceed directly to center’s preferred alternative donor (declared at start of trial for each patient) C. Observational Study of Search and Transplant Practice B. Direct to alternative donor source without a prolonged MUD search A. HLA-matched URD Search with intention to do 8/8 MUD HCT PRIMARY COMPARISON Expected: 40-50% HCT (>90% MUD <10% other donors) Expected: 60-70% HCT (70% HAPLO 15% CBT; 15% MMUD)

9. Difference in Haplo-MUD DFS Probabilities According to Donor Type: Negative Number Favors MUD(11 Retrospective Studies 2008-2016) None of these differences were statistically significant *Baker 2016 gave only median survivals: 245 days for haplo vs 293 days for MUD

10. Primary Objective Compare OS between the two arms (good and poor search prognosis)until 2 years The clock starts when a patient is confirmed to be evaluable (no suitable matched family member)

11. Secondary Objectives • Compare the cumulative incidence of receiving a transplant according to donor search prognosis • Describe barriers to achieving transplantation with different alternative stem cell sources and search strategies • Key gap in knowledge: <50% of patients who start a search receive a transplant and, while there are many assumptions about what happens, there is almost no hard data on what the barriers are and their relative impact • Important reason for including patients with a Less Likely search prognosis

12. Post-transplant Objectives • Compare survival, relapse, DFS, TRM, acute and chronic GVHD in patients transplanted for malignant diseasesaccording to initial search strategy and by alternative donor used • Describe survival and acute and chronic GVHD for patients with SAA and SCD according to initial search strategy and by the alternative donor used • QOL Substudy (n=286) – restricted to a more homogeneous cohort of AML and ALL CR1 and early stage MDS patients receiving matched unrelated donor or haploidentical transplants with specific conditioning and GVHD prophylaxis: to compare transplant outcomes, patient-reported QOL, number of hospital days, infections, immune reconstitution and late effects after transplantation

13. Eligibility and Enrollment • All ages, conditioning regimens, GVHD prophylaxis allowed • Diagnoses: AML, ALL, MDS, NHL, HL; SAA and SCD • Considered a suitable transplant candidate at the time of enrollment based on available data. Specific testing is not required • Intent to perform the transplant within the next 6 months • Intent to follow the recommended search algorithm based on biologic assignment • Does not preclude participation in any other study

14. Sample Size Calculation • Log-rank test, 2-sided significance for the primary comparison • Assumes 5% lost to follow up The analysis will adjust for racial/ethnic minority status and other relevant patient and disease characteristics

15. Safety Monitoring • 100 day survival after transplant for MUD Very Unlikely group • DSMB review triggered if 100 day mortality is predicted to exceed 15% for malignant disease or 10% for non-malignant disease

16. Study Design and Statistical Approach All of these interpretations assume that the outcome of patients who never get to transplant is inferior to the outcome of patients who do.

17. Accrual Feasibility • 1,732 subjects • 1,022 Very Likely and Very Unlikely donor search prognosis • If sites enroll 15% of potential patients and 60% have Very Likely or Very Unlikely, then can enroll 400-540 per year so 3 years enrollment. • 710 Less Likely donor search prognosis will also be enrolled and observed

18. CLINICAL EVENTS Transplant consult Patient HLA-typing sent Family HLA-typing sent No suitable MRD *Unrelated donor search *Alternative donor search (haplo, cord, mmURD) Donor identified Transplant occurs Transplant outcomes STUDY EVENTS Enrollment Evaluable Search algorithm based on likelihood of MUD (study-specific search report provided) Collect data about search QOL survey (n=286, 17%) TED or CRF QOL surveys

22. Potential future research samples • Scientific interest in research samples but BMT CTN funding is not available • Investigators would like to submit grants to fund sampling and research testing costs • Therefore, we would like to pre-consent patients to provide research samples • 30 mL pre-transplant and up to 6 times within the first 2 years • Patients will be notified verbally or in writing if this component of the protocol is activated • Samples are only drawn if additional funding is secured

23. Study Timeline • Protocol released to centers: ~March 2019 • First enrollment: ~May 2019 • (Accrual goal 1,732) • Enrollment completed: ~May 2022 • Primary analysis: ~Dec 2023

24. The Money • BMT CTN enrollment credit • Per evaluable patient: $742 (enrollment) + $257 (complete study forms) = $999 from BMT CTN • Per subject providing baseline QOL forms: add $320 from BMT CTN • TED vs. CRF is determined as if they were not on a BMT CTN study, except for those in QOL study (17%) • Per CRF: $135 baseline, $110 day 100 and $85 for 6, 12, 24 months = $500 from CIBMTR

25. Research billable tests/visits • None • There are no tests/visits required for this research study.