Starodub, Alexander

TPS3171 Background: Genetic alterations in fibroblast growth factor receptors 2 and 3 ( FGFR2/3 ) occur in nearly all cancer types. FGFR2 fusions and rearrangements occur in up to 10-15% of intrahepatic cholangiocarcinomas (iCCA) and alterations in FGFR3 occur in 15-30% of urothelial cancers. The clinical benefit from currently approved FGFR inhibitors (FGFRi) is often curtailed by development of acquired resistance, which may arise through on-target mutations in the FGFR2/3 kinase domain. Additionally, off-tumor effects on FGFR1 by pan-FGFRi can lead to hyperphosphatemia and consequently to dose reductions or dose holds. Thus, there is an unmet clinical need for a selective FGFR2/3 inhibitor that has clinical efficacy against activating alterations and resistance mutations without causing FGFR1-mediated hyperphosphatemia. CGT4859 is an orally bioavailable, ATP-competitive, reversible inhibitor of FGFR2/3, with potency against clinically relevant FGFR2/3 kinase domain mutations. In addition, CGT4859 demonstrates >140 fold selectivity over FGFR1, and shows robust efficacy in target altered in vivo tumor models without increases in serum phosphorus. Nonclinical pharmacokinetics (PK) and safety data support evaluating CGT4859 in a first-in-human, open-label, dose-escalation and signal-seeking Phase I/II study (NCT06777316). Safety, tolerability, PK, pharmacodynamics, and antitumor activity of CGT4859 will be assessed in adults with histologically confirmed unresectable or metastatic iCCA or other solid tumors with FGFR2/3 alterations. Methods: CGT4859 will be administered orally continuously in 28-day cycles to patients (N=~50) at a starting dose of 1 mg QD, and dose escalation will not exceed 40 mg QD as determined using a Bayesian optimal interval design with backfill (BF-BOIN). This approach will be used to guide dose escalation and establish the maximum tolerated dose (MTD) and recommended Phase 2 Dose (RP2D). BF-BOIN enables backfilling of participants to doses that are cleared for safety during the dose escalation, generating additional data on safety and tolerability below the MTD. Objective response rate (ORR) and disease control rate will be determined based on investigator assessment using RECIST v1.1. Phase II will enroll up to 4 cohorts, each enrolling ~15 patients. Proposed cohorts will include participants who have iCCA and are either FGFRi-naïve or FGFRi-exposed. Two additional cohorts with other advanced solid tumors harboring FGFR2/3 alterations may be included based on signals detected in dose escalation. The primary efficacy endpoint for Phase II is ORR per RECIST v1.1. The preclinical data support the study of CGT4859 in this patient population with solid tumors harboring FGFR2 and/or FGFR3 genetic alterations. The phase I dose escalation study is currently enrolling at sites in the United States. Clinical trial information: NCT06777316 .

4106 Background: Cancer stem cells are fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapy and targeted agents. Methods: A phase Ib/II multi-center study in mPDAC pts was performed to confirm the RP2D, PK profile and evidence of anticancer activity of napabucasin in combination with nabPTX and Gem. Pts received napabucasin 240 mg BID with weekly nabPTX 125 mg/m2 and gem 1000 mg/m2for 3 out of every 4 weeks until disease progression (PD) or other discontinuation criterion. Results: Of 71 intent to treat (ITT) pts enrolled, 49 (69%) were treatment-naïve and 22 (31%) received neoadjuvant treatment. There were no significant PK interactions, dose-limiting or unexpected toxicities. Most common adverse events (AEs) included grade 1 diarrhea/cramping, nausea and fatigue with grade 3 AEs noted in 12 pts: fatigue (8), electrolyte imbalance (2), diarrhea (1), dehydration (1), nausea (1) and weight loss (1). Among pts who received RECIST evaluation (60), disease control (DCR; CR+PR+SD) was observed in 55 (92%), with 1 CR (2%) and 26 PR (43%) (31 - 78% regression). Of 11 pts with non-evaluable disease, treatment stopped due to compliance (4), consent withdrawal (3), clinical PD (1), toxicity (1), insurance (1) and death (1). Among 71 ITT pts, DCR was observed in 55 (77%), with 1 CR (1.4%) and 26 PR (37%). Maturing median progression free survival and overall survival (OS) in ITT pts is >7.1 and >10.4 m, respectively. Conclusions: This study showed that napabucasin can be combined with nabPTX and gem, with encouraging signs of efficacy in mPDAC now being confirmed in a phase 3 study. Clinical trial information: NCT02231723. [Table: see text]

3529 Background: Cancer stem cells are considered to be fundamentally important for resistance, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinically, napabucasin sensitizes cancer cells to chemotherapy and targeted agents. Methods: A phase Ib/II multi-center study in mCRC pts was done to confirm the RP2D and signs of anti-cancer activity of napabucasin in combination with FOLFIRI +/- Bev. Pts received napabucasin 240 mg PO BID with bi-weekly FOLFIRI IV +/- Bev 5 mg/kg until disease progression or other discontinuation criterion. Results: 82 pretreated mCRC pts were enrolled (ITT); including 32 (39%) previously treated with FOLFIRI +/- bev. Of the 82 pts, 48 received FOLFIRI and 34 FOLFIRI plus bev in combination with napabucasin. There was no dose-limiting or unexpected toxicity or significant PK interactions. Most common adverse events (AEs) included grade 1/2 diarrhea, cramping, nausea, vomiting, fatigue and anorexia with grade 4 diarrhea in 1 pt and 27 pts with grade 3 AEs including: diarrhea (15), fatigue (5), dehydration (1), electrolyte imbalance (4), abdominal pain (1), vomiting (1) and weight loss (1), which resolved with dose reduction and supportive care. Disease control (CR+PR+SD) was observed in 55 of 66 pts who received RECIST evaluation (83%), with 1 CR (1.5%), 13 PR (20%) (33-100% regression) and 27 SD with tumor regression (41%). Conclusions: This phase Ib/II study confirmed that napabucasin can be safely combined with FOLFIRI +/- bev, and shows encouraging signs of efficacy in pretreated mCRC pts, including pts previously treated with FOLFIRI +/- bev. Clinical trial information: NCT02024607. [Table: see text]

593 Background: Cancer stem cells or stemness-high cancer cells are considered to be fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting Stat3-driven gene transcription. Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapeutics and targeted agents. Methods: This study was performed to assess signs of anti-tumor activity of napabucasin in combination with FOLFIRI +/- Bev in CRC pts. Napabucasin was administered at 240 mg BID. FOLFIRI (5-FU 400 mg/m2 bolus with 2400 mg/m2, irinotecan 180 mg/m2, and leucovorin 400 mg/m2 infusion) +/- Bev 5 mg/kg was administered biweekly until disease progression or other discontinuation criterion. pSTAT3 status of archival tumor tissue was assayed by immunohistochemistry using the H-score with pSTAT3highdefined as ≥ 5% pSTAT3+ cancer cells and tumor stroma staining at ≥ 2+ intensity. Results: 63 CRC pts with an average of >2 prior therapy lines were enrolled. No pharmacokinetic interactions or dose-limiting toxicity was observed. Most common adverse events (AEs) included grade 1/2 diarrhea, nausea, vomiting and fatigue. 25 pts had grade 3 AEs, including diarrhea (14), fatigue (4), dehydration (2), electrolyte imbalance (4), nausea (1) and weight loss (1) resolved with dose reduction and supportive care. Among 63 pts enrolled who received RECIST evaluation, disease control (CR+PR+SD) was observed in 49 pts (86%) with an overall response (CR+PR) of 28% with 1 pt achieving CR. Clinical trial information: NCT02024607. Conclusions: This phase Ib/II study suggests napabucasin may sensitize chemorefractory CRC to FOLFIRI +/- Bev. Encouraging signs of synergistic activity between napabucasin and FOLFIRI was observed in CRC pts regardless of pSTAT3 status.[Table: see text]

569 Background: BBI-608 is an oral first-in-class cancer stemness inhibitor that blocks STAT3-mediated transcription of cancer stemness genes. Potent anti-CSC activity was observed in vitro and in vivo,in mono and combination therapy. In phase I studies, BBI-608 was generally well tolerated with encouraging signs of anti-tumor activity. Methods: A phase Ib open label, multi-center study in pts with advanced CRC was undertaken to confirm the RP2D of BBI-608 in combination with FOLFIRI with or without BEV. BBI-608 was administered at 240 mg BID in combination with FOLFIRI (5-FU 400 mg/m2 bolus with 2400 mg/m2, irinotecan 180 mg/m2, and leucovorin 400 mg/m2infusion) with or without BEV 5 mg/kg, administered bi-weekly until progression of disease, unacceptable toxicity, or other discontinuation criterion was met. Results: 18 heavily pretreated pts with an average of > 3 prior lines of therapy of which 10 pts (56%) previously progressed on FOLFIRI were enrolled. Of the 17 pts evaluable for response, 8 pts received FOLFIRI and 9 pts received FOLFIRI with BEV in combination with BBI-608. Most common adverse events included grade 1 and 2 diarrhea, abdominal pain, nausea, vomiting and anorexia. No dose limiting toxicity or new adverse events were seen, and the safety profile was similar to that of each regimen as monotherapy. Grade 3 events related to protocol therapy included diarrhea occurring in 3 pts, fatigue in 2 pts and dehydration in 1 pt. All events resolved after dose reduction and/or start of anti-diarrheal medications. No significant pharmacokinetic interactions were observed. Disease control (PR+SD) was observed in 16 of 17 evaluable pts (94%) with 2 PR (per RECIST 1.1 criteria: 44% and 33% regression) and 14 SD (of which 13 (93%) had tumor regression < 25%). In the evaluable pts, median progression free survival was 5.54 months. Of 17 pts, 7 (41%) had prolonged SD of > 6 months. Conclusions: This phase Ib study confirmed that BBI-608 at 240 mg bid can be safely combined with FOLFIRI with and without BEV, and shows encouraging anti-tumor activity in heavily pretreated CRC pts, even in pts with prior progression on FOLFIRI-based therapy. Clinical trial information: NCT02024607.

Abstract Purpose: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). Experimental Design: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. Results: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. Conclusions: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. Clin Cancer Res; 21(15); 3420–7. ©2015 AACR.