A Phase I Study of Anti-ICOS Antibody MEDI-570 for Relapsed/Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL) and Angioimmunoblastic T-Cell Lymphoma (AITL) (NCI-9930)
Bibliographic record
Abstract
Background:T-follicular helper (TFH) cells are a novel CD4+ T-cell subset that participates in germinal center maintenance/proliferation. Proliferation of TFH is a postulated mechanism of pathogenesis for T-cell lymphomas (AITL, PTCL and others). The inducible T-cell costimulator (ICOS) is highly expressed in TFHand hence in AITL, PTCL FH type, and some cutaneous T cell lymphomas (CTCL) and follicular lymphomas (FL). MEDI-570 is a human afucosylatedIgG1 kappa monoclonal antagonistic antibody directed against ICOS, which binds to and eliminates ICOS expressing cells in preclinical in vivo models. We investigate the safety, pharmacokinetics (PK) and clinical activity of ICOS blockade by MEDI-570 in T-cell lymphomas. Methods: NCI-9930 is a Phase I study of MEDI-570 in R/R malignant lymphomas. It is a 3+3 study design that evaluated 5 dose levels . MEDI-570 was administered intravenously (IV) every 3 weeks for 12 cycles. Eligibility criteria included: age >18 years, ECOG <2, diagnosis of R/R PTCL, AITL, CTCL, mycosis fungoides, or FL, that have received and are refractory to at least 1 line of therapy (at least 2 lines of therapy and post autologous cell transplantation for FL), adequate organ functions and CD4+ T-cells >200 cells/uL (>100 for AITL). Primary endpoints are safety of MEDI-570, dose limiting toxicities (DLT)s and its recommended phase 2 dose (RP2D). Secondary endpoints include: pharmacokinetics (PK), overall response rate (ORR) based on Lugano classification and progression-free survival (PFS). Exploratory endpoints include various correlative studies. This study is supported by the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN) and Early Drug Development Opportunity Program (EDDOP) (NCT02520791). Results: As of June 2020, the dose escalation phase has been completed. Patients were enrolled and evaluable for safety and efficacy. Median age is 63 (range: 29-80), female/male ratio=5/13, histologic types consisted in AITL (n= 12, 71%), PTCL NOS (n=3, 18%) and CTCL (n=2, 12%). The median number of prior therapies were 7.5 (1 - 16), stage III/IV in 83%, prior autologous HCT in 18%. There were 4 partial remissions (PR) and 7 with stable disease (SD), all patients with AITL. Two patients (1 PR and 1 SD) remain on treatment. One patient completed treatment and remains in a stable PR for over a year without further treatment. One patient in PR underwent allogeneic hematopoietic transplantation (HCT) and remains in remission. The most common grade 3/4 AEs were decreased CD4+ T-cells as expected anemia (12%), hypophosphatemia (12%), thrombocytopenia (6%), infusion related reactions (6%). No DLTs were reported, and the maximum tolerated dose was not established. Initial PK analyses demonstrated that MEDI-570 systemic exposure increased in a dose-dependent manner, and a RP2D was determined. Peripheral blood flow cytometry analysis of T-cell subsets showed that MEDI-570 caused a rapid and sustained decrease in CD4+ T-cells. It also resulted in reductions in circulating of certain ICOS+ T-cells, especially on days 7-21 post treatment. Conclusion: MEDI-570 was safe, well tolerated and showed promising clinical activity in poor-risk refractory and heavily pretreated AITL. A RP2D was established. MEDI-570 results in sustained reduction of the targeted ICOS+T lymphocytes. The study continues enrolling in the expansion phase. Disclosures Chavez: Morphosys: Consultancy, Speakers Bureau; Merck: Research Funding; Bayer: Consultancy; BeiGene: Speakers Bureau; Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Consultancy; Verastem: Consultancy; Epizyme: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Pfizer: Consultancy. William:Dova: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; Merck: Research Funding; Kyowa Kirin: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Guidepoint Global: Consultancy. Brammer:Celgene Corporation: Research Funding; Seattle Genetics, Inc.: Speakers Bureau. Smith:Pharmacyclics: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; Acerta: Research Funding; BMS: Consultancy; Karyopharm: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; FortySeven: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy. Prica:astra zeneca: Honoraria; seattle genetics: Honoraria; Gilead: Honoraria. Zain:Kyowa Kirlin: Research Funding; Mundai Pharma: Research Funding; Seattle Genetics: Research Funding. Glenn:Genentech: Research Funding. Mehta-Shah:Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Kyowa Kirin: Consultancy; Innate Pharmaceuticals: Research Funding; Celgene: Research Funding; Genetech: Research Funding; C4 Therapeutics: Consultancy; Bristol Myers-Squibb: Research Funding. Boutrin:Astrazeneca: Current Employment, Current equity holder in private company. Zhao:Astrazeneca: Current Employment, Current equity holder in private company. Cheng:Astrazeneca: Current Employment, Current equity holder in private company. Standifer:Astrazeneca: Current Employment, Current equity holder in private company. Carlesso:Astrazeneca: Current Employment, Current equity holder in private company. Siu:Shatthucks: Research Funding; Symphogen: Consultancy, Research Funding; Tessa: Consultancy; Treadwell Therapeutics: Consultancy, Current Employment; Pfizer: Research Funding; Voronol: Consultancy; Rubius Therapeutics: Consultancy; Abbvie: Research Funding; Agios: Current equity holder in publicly-traded company; Arvinas: Consultancy; Astellas: Research Funding; AstraZeneca: Consultancy, Research Funding; Bayer: Research Funding; Boerhinger-Ingelheim: Research Funding; Bristol-Myers Squibb: Research Funding; Glaxo Smith Kline: Research Funding; Intensity Therapeutics: Research Funding; Navire: Consultancy; Novartis: Research Funding; Oncorus: Consultancy; Mirati: Consultancy, Research Funding; Roche/Genentech: Consultancy; Relay Therapeutics: Consultancy; Roche: Consultancy; Merck: Consultancy.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".