Citations

Abstract During development of pancreatic cancer, alternatively activated macrophages contribute to fibrogenesis, pancreatic intraepithelial neoplasia (PanIN) lesion growth, and generation of an immunosuppressive environment. Here, we show that the immunomodulatory agent pomalidomide depletes pancreatic lesion areas of alternatively activated macrophage populations. Pomalidomide treatment resulted in downregulation of interferon regulatory factor 4, a transcription factor for M2 macrophage polarization. Pomalidomide-induced absence of alternatively activated macrophages led to a decrease in fibrosis at PanIN lesions and in syngeneic tumors; this was due to generation of an inflammatory, immune-responsive environment with increased expression of IL1α and presence of activated (IFNγ-positive) CD4+ and CD8+ T-cell populations. Our results indicate that pomalidomide could be used to decrease fibrogenesis in pancreatic cancer and may be ideal as a combination treatment with chemotherapeutic drugs or other immunotherapies. Significance: These findings reveal new insights into how macrophage populations within the pancreatic cancer microenvironment can be modulated, providing the means to turn the microenvironment from immunosuppressive to immune-responsive.

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]

Abstract Background: X4P-001 is an orally bioavailable, selective, allosteric inhibitor of the chemokine receptor CXCR4, and has been shown to downregulate hypoxia inducible factor-2α (HIF-2α) and myeloid-derived suppressor cell (MDSC) trafficking in the tumor microenvironment. In multiple RCC xenograft models, the addition of X4P-001 to tyrosine kinase inhibitors (TKIs), including axitinib, has demonstrated increased efficacy and delayed onset of TKI resistance. Methods: This is an ongoing phase 1/2 open-label study of X4P-001 in combination with axitinib in patients (pts) with histologically confirmed clear cell RCC (ccRCC) who have received ≥1 prior systemic therapy. The Ph1 portion of the study evaluates safety, tolerability, PK, PD, and antitumor activity of the combination using a 3+3 dose escalation schema (escalating doses of X4P-001+ axitinib at 5 mg BID). The Ph2 portion is a single-arm expansion cohort evaluating this combination treatment in ~ 45 ccRCC pts. The radiologic assessment is performed every 8 weeks with central review. Results: As of 30 June, 2017, enrollment for the Ph1 portion of the study has been completed. Sixteen (16) pts were enrolled and the median age was 64 years (range 50-76). Pts had received a median of 2 prior lines of therapy (range 1-5). The doses tested were 200 mg BID, 400 and 600 mg QD of X4P-001 + axitinib. There were two dose-limiting toxicities (DLTs) observed at the X4P-001 600 mg QD dose level: one pt had multiple grade (G) 2 adverse events (AEs), including anorexia, cognitive disturbance, fatigue, nausea, vomiting, and somnolence; another pt had G3 dyspnea and fatigue. The MTD/RP2D was determined to be 400 mg QD of X4P-001 + axitinib. Treatment-related AEs (≥ 10%) of any grade were diarrhea, fatigue, hypertension, nausea, headache, anorexia, vomiting, dry eye, dysphonia, abnormal loss of weight, increased lipase, proteinuria, dry mouth, stomatitis, cognitive disorder, dysgeusia, and palmar-plantar erythrodysaesthesia syndrome. Treatment-related G3/4 AEs (≥ 10%) were hypertension. In addition, one pt had SAE due to G2 diarrhea and G2 creatinine elevation. Drug exposures (AUC0-24hr) at steady state (SS) are similar for 200 mg BID and 400 mg QD dose. Mean Cmax and AUC0-24hr at SS increased approximately 1.6- and 1.9-fold, respectively, from 400 mg to 600 mg QD dose. Leukocyte mobilization is a well-established surrogate marker for CXCR4 inhibition. At both 400 mg and 600 mg daily dose levels, X4P-001 demonstrated approximately 2 to 2.5-fold increase of WBC (range: 1.4-4.7 fold) and nearly 4-fold increase of CD34+ progenitor cells (range: 1.8-6.4 fold). The peak elevation of both markers occurred around 2 to 4 hours following dosing. Of the 12 clinically evaluable pts, 3 had confirmed partial response, 8 had stable disease, and 1 had progressive disease. As of 30 June 2017, 9 pts remain on study and median duration on treatment was 27 weeks (range 7.4-60). Conclusions: The combination treatment is well tolerated at a dose of 400 mg QD of X4P-001 + axitinib with preliminary evidence of clinical activity. The doses used in this phase I study were biologically active in inhibiting CXCR4 in peripheral blood as demonstrated by elevating WBC and CD34+ cell counts. The Ph2 portion of the study is ongoing. Citation Format: Michael Atkins, Richard Joseph, Thai Ho, Ulka Vaishampayan, Sarah Ali, Marc Matrana, Robert Alter, Jeff Edenfield, Yan Wang, Sarah Blanchette, Lu Gan, David McDermott. A phase 1 dose-finding study of X4P-001 (an oral CXCR4 inhibitor) and axitinib in patients with advanced renal cell carcinoma (RCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B201.

677 Background: Napabucasin a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting Stat3-driven gene transcription. Preclinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. In a phase 1 study, napabucasin monotherapy was well tolerated with encouraging signs of anti-tumor activity at the RP2D of 500 mg BID. Methods: The current open-label, multi-center study includes phase II expansion in pts with refractory, K- Raswt mCRC to confirm safety and anti-tumor activity of napabucasin administered orally at 480mg BID in combination with panitumumab (6mg/kg bi-weekly). Results: 72 pts were enrolled, 48 pts were evaluable by RECIST of which 7 (15%) and 41 (85%) had 2 or >3 prior treatment lines, respectively. Of the 48 evaluable pts, 64.6% (31/48) were previously treated with an anti-EGFR agent. No new adverse events (AEs) were observed and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Among 48 pts enrolled who received RECIST evaluation, Disease Control Rate (DCR) was observed in 25 pts (52.1%) of which 3 pts achieved PR (6%) and 22 pts achieved SD (45%). Among 31 pts previously treated with anti-EGFR therapy, DCR was observed in 15 pts (48%) compared with DCR of 59% observed in 10 out of 17 anti-EGFR naïve pts receiving a scan. Conclusions: This phase II study confirmed that napabucasin can be safely combined with panitumumab at full dose and shows encouraging anti-tumor activity in pts with K- Ras wt mCRC, regardless of prior anti-EGFR exposure, suggesting that napabucasin may sensitize pts to repeat anti-EGFR therapy. Clinical trial information: NCT01776307. [Table: see text]