This is a multicenter, open-label, first-in-human Phase 1 study evaluating the anti-PD-1 antibody TSR-042 in patients with advanced solid tumors who have limited available treatment options as determined by the Investigator. The study will be conducted in 2 parts.
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This is a nonrandomized study of ruxolitinib in combination with a standard multi-agent chemotherapy regimen for the treatment of B-ALL. The backbone multi-agent therapy is a modified augmented Berlin-Frankfurt-Münster (aBFM) regimen that is used in the Children's Oncology Group (COG) Study AALL1131 (control arm) for patients with de novo B-ALL. This chemotherapy backbone is the current standard of care for patients with NCI HR B-ALL. Ruxolitinib will be administered in conjunction with all post-Induction phases of the aBFM regimen.
Subjects with de novo B-ALL, aged 1 to 21 years at the time of diagnosis, will be evaluated for genetic eligibility during the Induction phase of a 4-drug regimen (modified aBFM or equivalent) received on Study AALL1131 (or its successor study) or with a similar 4-drug regimen. Genetic analysis of baseline diagnostic bone marrow aspirate or peripheral blood samples will be performed at COG ALL reference laboratories. Eligible genetic abnormalities include the following:
Rearranged CRLF2 (CRLF-R)
Mutations in JAK1 or JAK2 (JAK+)
Other alterations involving the JAK pathway (eg, JAK2 fusions, EPO-R fusions, SH2B3 deletions, IL7RA mutations)
At the end of Induction therapy, MRD will be assessed from bone marrow sampling via flow cytometric analysis, per the standard of care. For the purposes of this Protocol, end-Induction MRD status is defined as + or (-) as follows:
MRD 0.01% is MRD+
MRD < 0.01% is MRD(-)
Cohort assignment will be based upon genetic analysis and end-Induction MRD status, as follows:
Cohort A: CRLF2-R and JAK+ with MRD+
Cohort B: CRLF2-R and JAK- with MRD+
Cohort C: other JAK pathway alterations (+/- CRLF2-R) with MRD+
Cohort D: subjects otherwise eligible for Cohorts A, B, or C with MRD(-)