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Two randomized, double‐blind, placebo‐controlled studies demonstrated responses (≥50 000/μL) to fostamatinib in adults with long‐standing immune thrombocytopenia (ITP). The long‐term safety and efficacy of fostamatinib were evaluated in a follow‐on, open‐label extension (OLE) study. Patients received double‐blind fostamatinib in the randomized trials, and responders continued the same dose, 100 to 150 mg BID, in the OLE study. Nonresponders received 100 mg BID for 4 weeks and could escalate to 150 mg BID at week 4. Endpoints included stable response, platelet count ≥50 000/μL at 4/6 biweekly (randomized trials) or 2/3 monthly visits (OLE), and overall response, ≥1 platelet count ≥50 000/μL during weeks 1 to 12. A total of 146 patients received fostamatinib including 123 in the OLE study. Median treatment duration was 6.7 months. Baseline median ITP duration was 8 years and median platelet count was 16 000/μL; prior treatments included thrombopoietic (TPO) agents (47%), splenectomy (35%), and rituximab (32%). Twenty‐seven (18%) patients achieved a stable response with median duration of >28 months and a median platelet count of 89 000/μL. Sixty‐four (44%) patients achieved an overall response (including stable responders) with a median platelet count of 63 000/μL and a median response duration of >28 months. Twenty‐four of 71 (34%) patients who had failed TPO agents achieved overall responses to fostamatinib. The most common adverse events (AEs) were diarrhea, hypertension, nausea, epistaxis, and abnormal liver function tests. Most AEs were mild/moderate and resolved or were managed with dose reduction, dose interruption, and/or secondary medication. Almost half of the patients achieved an overall response, and most of these maintained their responses for >2 years. No new or increased frequency of AEs was seen at up to 31 months of treatment.

e16287 Background: Pancreatic ductal adenocarcinoma (PDA) has been refractory to therapeutic targeting of the immune microenvironment. In preclinical work, IL-1β was upregulated in PDA tumors, and in mouse models, IL-1β expression led to activation of pancreatic stellate cells and immunosuppression. We hypothesize that blockade of IL-1β and PD-1 will result in significant alterations in immune and fibroblast subsets within the PDA microenvironment. Methods: We conducted an open-label multicenter Phase Ib study evaluating gemcitabine and nab-paclitaxel with canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) mAb, and spartalizumab (PDR001), a mAb directed against human PD-1. 10 subjects with untreated metastatic PDA and RECIST measurable disease were enrolled. The primary objective was to identify a recommended phase II/III dose by evaluating the incidence of DLTs in the first 56 days. All subjects underwent baseline and on-study tissue and blood collection for extensive exploratory correlative studies. Secondary objectives including safety and tolerability and preliminary assessment of clinical activity. Results: 10 subjects were enrolled between November 2020 and March 2021. 6 out of 10 were evaluable for the dose confirmation. In the dose confirmation analysis there were no dose limiting toxicities (DLTs) and the recommended Phase II/III dose was established as; gemcitabine (1000 mg/m2 IV) and nab-paclitaxel (125 mg/m2 IV) on day 1,8,15; canakinumab (250 mg via subcutaneous injection) and spartalizumab (400 mg IV) on day 1; of each 28 day cycle. Adverse events were consistent with those seen with chemotherapy and were predominately hematologic. A preliminary efficacy analysis confirms 1 PR and 7 pts with SD. Two of the 7 pts have been treated for 11 and 12 cycles, respectively, without progression. Activation of CD8 T cells in peripheral blood and increased serum levels of IFN-induced chemokines CXCL9/10 were observed in patient samples. Using an in vitro suppression assay, we showed that baseline serum, from patients deriving clinical benefit, could induce myeloid derived suppressor cells, but that this effect was abrogated with treatment. Single cell transcriptional profiling also revealed treatment-dependent shifts in T cell activation state and myeloid cells in the tumors of patients experiencing clinical benefit. Conclusions: In this Phase Ib study, we established the Phase II/III dose of canakinumab and spartalizumab with chemotherapy in first line metastatic PDA. Translational studies suggest putative biomarkers that may help identify responding pts. This novel combination is being evaluated in a randomized Phase II/III study through the Precision Promise clinical trial network. Clinical trial information: NCT04581343.

TPS4188 Background: The success rate of drug development in PDAC is disappointingly low.PrP is a transformative, adaptive platform clinical trial designed to continuously evaluate many novel therapeutic options while increasing the probability that patients (pts) are randomized to effective experimental therapies. It cultivates enhanced cooperation among groups representing pts advocacy, pharmaceutical companies, academia, and the FDA. This patient-centric study aims to become the largest Phase 3 registrational study in PDAC and represents a fundamental shift in drug development for PDAC in the United States (US). Methods: PrP (NCT04229004) is a platform clinical trial sponsored by the Pancreatic Cancer Action Network (PanCAN), developed based on the FDA 2020 guidance document regarding "complex innovative designs" in registration trials https://www.fda.gov/media/130897/download . It utilizes adaptive randomization and other Bayesian statistical innovations provided by Berry Consultants LLC, including the “time machine” which uses all previously randomized controls for each arm, suitably adjusted for line of therapy and the time period of the arm. Focused on 1st and 2nd line treatment of mPDAC, PrP uses an adaptive platform design with randomization to one of 2 control arms (gemcitabine + nab-paclitaxel (GA) or mFOLFIRINOX, 30% of pts) or experimental therapy (70% of pts). Candidate experimental arms are reviewed by an Arm Selection Committee based on validity of the treatment target and strength of the pre-clinical and clinical data. The primary endpoint is overall survival (OS). Pts undergo pre- and on-treatment biopsies with state-of-the-art genomic, transcriptomic, and immune analysis, along with a serial collection of blood-based research samples. Pts are managed using novel supportive care techniques; PrP contains 3 sub-protocols evaluating quality of life, sarcopenia, and actigraphy. PrP launched in 2020 and has enrolled > 130 pts; 30 US sites have been selected with 17 currently active. Current experimental arms include: (i) GA + Pamrevlumab, an anti-CTGF Ab, (ii) Racemetyrosine monotherapy, a cancer metabolism-based therapy (for follow-up of patients) and (iii) an immuno-oncology arm in activation. Other arms are in the planning stages. Compared to traditional designs, PrP offers several advantages: multiple investigational treatments evaluated in parallel over time; ̃175 pts per experimental arm required to initiate a regulatory registration; and continuous learning from every patient, resulting in significant savings of time and resources. PrP has created an entirely new learning environment for accelerating drug development in PDAC. Clinical trial information: NCT04229004.

Trends in clinical trials for pancreatic cancer between 2011-2020 were tracked in the Pancreatic Cancer Action Network database originally designed to assist in identifying open trials for eligible patients. More than 125 trials specific for pancreatic cancer or including no more than one additional cancer type have been open each year, the majority for patients with a diagnosis of pancreatic adenocarcinoma (PAC). The trends indicate an active and progressive pancreatic cancer research community and include an increasing number of trials for previously treated patients, the emergence of trials for post-adjuvant or maintenance therapy, an increasing number of research-intensive phase 0 trials, increasing seamless phase I/II and II/III trials to improve efficiency, and an increasing number of phase III trials despite historical failures. Trials were analyzed by treatment type and included trials to optimize standard chemotherapy or radiation therapy, trials targeting tumor pathways, the stroma, or the immune system, biomarker-specified trials, and a miscellaneous category of trials testing tumor metabolism, complementary medicine approaches, or alternate energy sources. There was a dramatic increase in immunotherapy trials over this time. Several biomarker-specified trials were initiated, and FDA approval was obtained for biomarker-specified targeted agents, many in a tissue-agnostic setting, indicating an increase in a precision medicine approach to pancreatic cancer treatment. An increasing number of trials tested non-standard approaches, many which progressed to phase III. The trends suggest an encouraging trajectory of pancreatic cancer clinical research.

Spleen tyrosine kinase (Syk) signaling is central to phagocytosis‐based, antibody‐mediated platelet destruction in adults with immune thrombocytopenia (ITP). Fostamatinib, an oral Syk inhibitor, produced sustained on‐treatment responses in a phase 2 ITP study. In two parallel, phase 3, multicenter, randomized, double‐blind, placebo‐controlled trials (FIT1 and FIT2), patients with persistent/chronic ITP were randomized 2:1 to fostamatinib (n = 101) or placebo (n = 49) at 100 mg BID for 24 weeks with a dose increase in nonresponders to 150 mg BID after 4 weeks. The primary endpoint was stable response (platelets ≥50 000/μL at ≥4 of 6 biweekly visits, weeks 14‐24, without rescue therapy). Baseline median platelet count was 16 000/μL; median duration of ITP was 8.5 years. Stable responses occurred in 18% of patients on fostamatinib vs. 2% on placebo (P = .0003). Overall responses (defined retrospectively as ≥1 platelet count ≥50 000/μL within the first 12 weeks on treatment) occurred in 43% of patients on fostamatinib vs. 14% on placebo (P = .0006). Median time to response was 15 days (on 100 mg bid), and 83% responded within 8 weeks. The most common adverse events were diarrhea (31% on fostamatinib vs. 15% on placebo), hypertension (28% vs. 13%), nausea (19% vs. 8%), dizziness (11% vs. 8%), and ALT increase (11% vs. 0%). Most events were mild or moderate and resolved spontaneously or with medical management (antihypertensive, anti‐motility agents). Fostamatinib produced clinically‐meaningful responses in ITP patients including those who failed splenectomy, thrombopoietic agents, and/or rituximab. Fostamatinib is a novel ITP treatment option that targets an important mechanism of ITP pathogenesis.

Background: Drug development in PDAC has been disappointing with an extremely low trial success rate despite considerable effort. PrP is a transformative, adaptive clinical trial platform that attempts to correct this by continuously and rapidly evaluating novel therapeutic options while maximizing the probability of patient (pt) randomization to an experimental treatment and nurturing enhanced cooperation among groups representing pt advocacy, pharmaceuticals, translational/clinical academia, and the FDA. This patient-centric study represents a fundamental shift in drug development for PDAC in the United States and aims to become the largest Phase 2/3 registrational study ever launched in this disease. Methods: PrP (NCT04229004) is a clinical trial platform sponsored by the Pancreatic Cancer Action Network (PanCAN) and funded solely through non-government sources. The protocol was finalized based on the FDA 2020 guidance document regarding "complex innovative designs" in registration trials https://www.fda.gov/media/130897/download. It utilizes adaptive randomization along with several trial design and Bayesian statistical innovations provided by Berry Consultants LLC. All pts undergo pre-and on-treatment biopsies with state-of-the-art genomic, transcriptomic, and immune analysis, along with collection of blood samples for research purposes throughout the study. Pts are managed using novel standardized supportive care techniques, and PrP contains 3 sub-protocols involving quality of life, sarcopenia and actigraphy. PrP was launched in 2020, and currently includes 20 US sites. Focused on both 1st and 2nd line treatment of metastatic PDAC, PrP uses an adaptive platform design with 30% of pts randomized between one of the 2 standard of care control arms (gemcitabine + nab-paclitaxel and mFOLFIRINOX) and 70% to experimental arms, currently either SM-88, a cancer metabolism-based agent (Tyme Inc); or Pamrevlumab, an antibody inhibiting the activity of the connective tissue growth factor (Fibrogen Inc.) The study is ongoing with >100 pts enrolled to date. The Data and Safety Monitoring Committee regularly reviews the data and continues to recommend that the trial proceeds as planned. New study arms will be added after review by an Arm Selection Committee that assesses the validity of the treatment target and the adequacy of the preexisting pre-clinical and clinical data. An additional experimental arm is anticipated in 2021. Conclusion: Compared to traditional trial designs, PrP offers several advantages: multiple investigational treatments can be evaluated in parallel over time; only ~ 175 pts per experimental arm required to initiate a regulatory registration; and increased learning from every patient during the trial, altogether resulting in both time saving and a 30-50% cost saving. In effect, PrP has created an entirely new “learning community” and can substantially accelerate drug development for PDAC. Citation Format: Vincent J. Picozzi, Anne-Marie Duliege, Anirban Maitra, Manuel Hidalgo, Andrew Eugene Hendifar, Gregory L. Beatty, Sudheer Doss Doss, Regina Deck, Lynn M. Matrisian, Julie Fleshman, Diane M. Simeone. Precision Promise (PrP): An adaptive, multi-arm registration trial in metastatic pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-050.

Immune thrombocytopenia (ITP) is an autoimmune disease associated with substantial heterogeneity and varying outcomes. Significant bleeding, including intracranial hemorrhage, is a persistent risk for patients with ITP, along with cardiovascular disease. ITP has also been associated with decreased patient functionality and quality of life. The primary goal of ITP therapy is to lower the risk of bleeding and associated complications by raising platelet counts to levels that provide adequate hemostasis with minimal treatment-related toxicity. Current first-line treatments include corticosteroids, as well as intravenous and anti-D immunoglobulin. Despite the availability of several second-line options, the need for additional treatment options that can provide a stable, long-term response with few adverse effects is critical and ongoing. Fostamatinib disodium hexahydrate is an oral spleen tyrosine kinase inhibitor that produces a rapid, durable response in patients who have failed one or other treatments. Additionally, fostamatinib is well tolerated, and adverse effects can be actively mitigated through dose reduction, dose interruption, or standard therapeutic approaches.