Preliminary Evidence Of Clinical Activity Research Articles

REGN5458, a Bispecific BCMAxCD3 T Cell Engaging Antibody, Demonstrates Robust In Vitro and In Vivo Anti-Tumor Efficacy in Multiple Myeloma Models, Comparable to That of BCMA CAR T Cells

Improving therapies for multiple myeloma (MM) remains a high medical need because of the significant morbidity and mortality of the disease. Targeted immunotherapies represent a promising opportunity to fill this clinical need. B cell maturation antigen (BCMA) is an attractive cell-surface target for MM due to its consistent expression on MM patient malignant plasma cells and expression limited in normal tissue primarily to plasma cells. Redirection of a patient's T cells to recognize tumors by CD3-binding bispecific molecules or through the generation of chimeric antigen receptor (CAR) T cells, has shown preliminary evidence of clinical activity. Bispecific antibodies concurrently engage a tumor antigen on cancer cells and the CD3 signaling machinery on T cells, bringing the tumor cell and T cell into proximity and facilitating T cell activation and tumor cell killing. By contrast, CAR T cell therapy involves re-infusion of the patient's own T cells after ex vivo engineering to express CARs targeting tumor antigens and triggering T cell signaling.Here we describe the generation of REGN5458, a human bispecific antibody that binds to BCMA and CD3. In vitro, REGN5458 efficiently activates T cells and induces polyclonal T cell killing of myeloma cell lines with a range of BCMA cell-surface densities, and also induces cytotoxicity of primary human plasma cells. Similar to gamma-sectretase inhibitors, incubation of myeloma cell lines with REGN5458 increased surface levels of BCMA. In xenogenic studies, after BCMAhigh NCI-H929 and BCMAlow MOLP-8 MM cells were co-implanted with PBMC and grown subcutaneously in immunodeficient NOD/SCID/L2Rgamma-deficient (NSG) mice, REGN5458 doses as low as 0.4 mg/kg significantly suppressed the growth of both tumors. Using aggressive, systemic xenogenic tumor models, in which NSG mice were engrafted with PBMC and intravenously injected with BCMAhigh OPM-2 cells or BCMAlow MOLP-8 cells expressing luciferase, REGN5458 reduced tumor burden and suppressed tumor growth at doses as low as 0.4 mg/kg. In immunocompetent mice genetically engineered to express human CD3, REGN5458 inhibited the growth of syngeneic murine tumors expressing human BCMA at doses as low as 0.04 mg/kg. Finally, as REGN5458 binds to cynomolgus CD3 and BCMA and mediates cytotoxicity of primary cynomolgus plasma cells, the pharmacology of REGN5458 was evaluated in cynomolgus monkeys. REGN5458 administration was well-tolerated, resulting in a mild inflammatory response characterized by transiently increased CRP and serum cytokines. Importantly, REGN5458 treatment led to the depletion of BCMA+ plasma cells in the bone marrow, demonstrating cytotoxic activity in non-human primates.The anti-tumor efficacy of REGN5458 was compared to BCMA-specific CAR T cells using 2nd generation CAR lentiviral constructs containing a single-chain variable fragment binding domain from REGN5458's BCMA binding arm and 4-1BB and CD3z signaling domains. Human PBMC-derived T cells were transduced to express this CAR and expanded. Both REGN5458 and the BCMA CAR T cells demonstrated similar targeted cytotoxicity of myeloma cell lines and primary patient blasts in vitro, and were capable of clearing established systemic OPM-2-luciferase myeloma tumors in NSG mice, but with different kinetics: treatment with REGN5458 resulted in rapid clearance of tumors within 4 days, whereas treatment with BCMA CAR T cells allowed tumors to continue to grow for 10-14 days following injection before rapidly inducing tumor clearance. Thus, REGN5458 exerts its therapeutic effect rapidly after injection, using effector T cells that are already in place. In contrast, BCMA CAR T cells require time to traffic to the tumor site and expand, before exerting anti-tumor effects.Collectively, these data demonstrate the potent pre-clinical anti-tumor activity of REGN5458 that is comparable to that of CAR T cells, and provide a strong rationale for clinical testing of REGN5458 in patients with MM. DisclosuresDilillo:Regeneron Pharmaceuticals: Employment. Olson:Regeneron Pharmaceuticals: Employment. Mohrs:Regeneron Pharmaceuticals: Employment. Meagher:Regeneron Pharmaceuticals: Employment. Bray:Regeneron Pharmaceuticals: Employment. Sineshchekova:Regeneron Pharmaceuticals: Employment. Startz:Regeneron Pharmaceuticals: Employment. Retter:Regeneron Pharmaceuticals: Employment. Godin:Regeneron Pharmaceuticals: Employment. Delfino:Regeneron Pharmaceuticals: Employment. Lin:Regeneron Pharmaceuticals: Employment. Smith:Regeneron Pharmaceuticals: Employment. Thurston:Regeneron Pharmaceuticals: Employment. Kirshner:Regeneron Pharmaceuticals: Employment.

Early Results from a Biomarker-Directed Phase 2 Trial of Sy-1425 in Combination with Azacitidine or Daratumumab in Non-APL Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Early Results from a Biomarker-Directed Phase 2 Trial of Sy-1425 in Combination with Azacitidine or Daratumumab in Non-APL Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Abstract CT129: The THINK clinical trial: Preliminary evidence of clinical activity of NKG2D chimeric antigen receptor T cell therapy (CYAD-01) in acute myeloid leukemia

Abstract NKG2D is a receptor with specificity for a broad range of stress ligands expressed on the majority of tumors (MICA, MICB and ULBP1-6). In vivo preclinical studies in acute myeloid leukemia (AML), ovarian, multiple myeloma (MM) and pancreatic cancer models all showed potent efficacy of T cells engrafted with a NKG2D Chimeric Antigen Receptor (CAR) indicating the possible effectiveness of CYAD-01 (a.k.a NKR-2) in the clinic. To evaluate the susceptibility of several malignancies to NKG2D ligand targeting in a clinical setting, and the safety of CYAD-01, an open-label phase I THINK (THerapeutic Immunotherapy with NKR-2, NCT03018405) trial was initiated. CYAD-01 was administered three successive times with 2-week intervals, and without prior lymphodepletive conditioning, in refractory or relapsed patients with different metastatic solid tumors and hematological malignancies (AML/MDS and MM), which failed from standard treatments. The study was designed to have two segments. The first dose escalation segment (3+3 design) includes three dose levels: 3x108, 1x109 and 3x109 CYAD-01 per injection, in both solid and hematological arms. The second, open-label phase I expansion segment of the study will evaluate the recommended dose in each tumor type. By December 2017, within the solid tumor arm, 4 patients had received three CYAD-01 administrations at dose-level 1 and three patients had received three CYAD-01 administrations at dose-level 2 and completed the safety period with no DLT occurrence. Within the hematologic arm, two AML patients and 1 MM patient have received the three CYAD-01 administrations at dose-level 1 and completed the safety period with no dose-limiting toxicity (DLT) occurrence. One relapsed AML patient to salvage CLAG-M chemotherapy reached a morphologic leukemia-free state (MLFS) after the CYAD-01 treatment, and resolution of symptoms with improved hematopoiesis at 3 months follow up at which time he started conditioning therapy for allo-HSCT. At 3 months post allo-HSCT, the patient is in complete remission with 100% donor chimerism. Interestingly, even at this early stage of the evaluation, there is variation in the phenotype of the CYAD-01 cells (e.g. CD4/CD8 ratio) and an early observation of a relative increase in the systemic levels of SDF-1 and RANTES in the patient who achieved MLFS. In summary, we report the first objective response to CAR-T in r/r AML using CYAD-01 without preconditioning chemotherapy and with no significant toxicities, highlighting the potential of targeting NKG2D ligands in AML. Citation Format: David A. Sallman, Jason B. Brayer, Xavier Poire, Tessa Kerre, Philippe Lewalle, Eunice S. Wang, Bikash Verma, Eytan Breman, Marco Davila, Nathalie Braun, Caroline Lonez, David E. Gilham, Frédéric F. Lehmann. The THINK clinical trial: Preliminary evidence of clinical activity of NKG2D chimeric antigen receptor T cell therapy (CYAD-01) in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT129.

Abstract B201: A phase 1 dose-finding study of X4P-001 (an oral CXCR4 inhibitor) and axitinib in patients with advanced renal cell carcinoma (RCC)

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.

Abstract 5593: Inhibition of A2AR induces anti-tumor immunity alone and in combination with anti-PD-L1 in preclinical and clinical studies

Abstract Adenosine signaling via A2A receptor (A2AR) on immune cells suppresses anti-tumor immunity and limits the efficacy of immunotherapy, chemotherapy, CAR-T, and vaccines. CPI-444 is a potent and selective oral A2AR antagonist. Daily treatment of mice with CPI-444 led to dose-dependent inhibition of tumor growth in multiple syngeneic tumor models. Combining CPI-444 with anti-PD-L1 treatment synergistically eliminated tumors in up to 90% of treated mice, including restoration of immune responses in models that are poorly responsive to anti-PD-1 or anti-PD-L1 monotherapy. We have initiated a Phase 1/1b clinical trial to examine safety, tolerability, biomarkers, and preliminary efficacy of CPI-444 as a single agent and in combination with the anti-PD-L1 antibody, atezolizumab, in patients with non-small cell lung, melanoma, renal, triple negative breast, and other (bladder, prostate, head and neck, colorectal) tumors. Step 1 of the trial focused on determining the optimal dose and schedule for CPI-444; Step 2 is currently evaluating the efficacy of optimal CPI-444 dosing alone and with atezolizumab. In 48 patients treated in Step 1, CPI-444 was well tolerated with 1 Grade 3 or 4 treatment related adverse events. Preliminary evidence of clinical activity was observed in patients treated with single agent CPI-444, including patients who previously failed anti-PD-1 therapy. A pCREB-based pharmacodyamic assay showed that 100 mg, BID dose of CPI-444 resulted in a complete, sustained inhibition of A2AR on circulating immune cells. CPI-444 treatment alone or in combination with atezolizumab resulted in increased frequency of circulating CD8+PD-1+ cells and memory/effector subsets of CD4+ and CD8+ T cells. Substantial changes in TCR repertoire (Morisita Index <0.9) were observed in both anti-PD-1 native and refractory patients and correlated to patient responses. CD73 expression, CD8+ infiltration, TREG distribution, and gene expression signatures are currently being evaluated in serial tumor biopsy specimens and will be presented. In total, this shows that CPI-444 is well tolerated in cancer patients, exhibits functional inhibition of adenosine signaling, and treatment is associated with activation of anti-tumor immunity and clinical activity. Citation Format: Stephen Willingham, Andrew Hotson, Po Ho, Carmen Choy, Kim Walter, Erik Yusko, Sharon Benzeno, Ginna Laport, Richard Miller, Ian McCaffery. Inhibition of A2AR induces anti-tumor immunity alone and in combination with anti-PD-L1 in preclinical and clinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5593. doi:10.1158/1538-7445.AM2017-5593

Phase 1 study to evaluate the safety and tolerability of MEDI4736 (durvalumab, DUR) + tremelimumab (TRE) in patients with advanced solid tumors.

3069 Background: DUR is a human IgG1 monoclonal antibody (mAb) that blocks PD-L1. TRE is a human IgG2 mAb inhibitor of CTLA-4. Blocking these checkpoints can result in antitumor activity in some solid tumors. The targets for DUR and TRE are non-redundant, providing sound rationale for clinical testing of the combination. Methods: This is an ongoing Phase 1, multicenter, open label study (NCT01975831) with a dose escalation (3+3 design) and subsequent expansion phase. Patients (pts) with renal cell carcinoma (RCC), cervical (CC), colorectal (CRC), non-triple-negative breast (NTNBC), ovarian (OC), non-small cell lung, or head and neck cancer are eligible. Primary endpoints are safety/tolerability and identification of maximum tolerated dose (MTD) of the combination. Secondary objectives include tumor response and progression-free/overall survival. Results: As of 16 Dec 2016, 105 pts were treated. DUR 1500 mg every 4 weeks (Q4W) and TRE 75 mg Q4W X 4 was the regimen used for opening the expansion phase. Dose-limiting toxicities were reported in 4 pts: diarrhea, colitis, abnormal liver function tests (abn LFTs), and hyponatremia. The majority of treatment-related AEs (TRAEs) were Grades (Gr) 1 and 2. TRAEs ≥ Gr 3 were reported in 12 pts; the majority were diarrhea/colitis (n = 5) and abn LFTs (n = 4) and responded to established treatment algorithms. There was 1 Gr 5 TRAE: multi organ failure. No new toxicities were identified. The preliminary responses by tumor type with n ≥ 10 pts are shown in the table below. Responses were seen in OC and RCC at the Cohort 2 dose escalation level (DUR 1/TRE 3 mg/kg). There were 4 cases of SD > 24 weeks: CC, n=2; CRC, n=1; OC, n=1. PD-L1 status was not tested. Conclusions: The DUR + TRE combination has a manageable safety profile, with preliminary evidence of clinical activity. These data support continued study of the combination therapy; the study is ongoing. Clinical trial information: NCT01975831. [Table: see text]

Abstract P2-08-06: A phase 1 study of RAD1901, a novel, oral selective estrogen receptor degrader, for the treatment of ER-positive advanced breast cancer

Abstract Background: The majority of breast cancers are defined as estrogen receptor positive (ER+) breast cancer. Despite availability of standard therapies, such as aromatase inhibitors, many women eventually relapse with aggressive disease due to acquisition of endocrine resistance, including ESR1 mutations. To help address some of the challenges associated with current therapies including exposure limitations and intramuscular administration, we have developed RAD1901, a novel, non-steroidal, oral selective estrogen receptor degrader (SERD). Preclinical studies with RAD1901 have demonstrated a dose dependent degradation of ER consistent with a SERD mechanism of action. In multiple in vivo models of breast cancer, including patient-derived xenograft models that are sensitive or resistant to standard endocrine therapies, RAD1901 has anti-tumor efficacy both as a single agent and in combination with palbociclib and everolimus. Importantly, RAD1901 has shown superior efficacy compared to fulvestrant in a number these models including those harboring and ESR1 mutation. Methods: RAD1901-005 is a Phase 1 study currently enrolling ER+ advanced metastatic breast cancer patients (ClinicalTrials.gov identifier: NCT02338349) with a dose escalation cohort based on a standard 3+3 design followed by a safety expansion cohort at a tolerated dose. Key inclusion criteria include postmenopausal women aged 18 years or older, with advanced ER+, HER2-negative breast cancer, who have received ≤ 2 prior chemotherapy regimens in the metastatic setting and > 6 months of prior endocrine therapy. In addition, circulating tumor DNA (ctDNA) was evaluated to determine ESR1 mutation status and to correlate it with clinical response. Results: As of the cut-off date in March, 13 patients were enrolled in the dose escalation part of the study (3+3 design) at doses of 200 mg qd, 400 mg qd and 600 mg qd. RAD1901 exposure was dose dependent and the PK profile was comparable to PK data from a previous study in healthy volunteers. RAD1901 was well tolerated with the most common adverse events being low-grade nausea and dyspepsia. No DLTs were observed. A safety expansion cohort (Part B, n=20) was opened. At the cut-off date 4 of the 13 patients had been on study 4 or more months. Updated outcomes and biomarker data, including ctDNA, will be presented at the meeting. Conclusion: RAD1901, a novel, non-steroidal, oral SERD, is well-tolerated with manageable adverse effects, and is associated with preliminary evidence of clinical activity in patients with advanced ER+ advanced postmenopausal breast cancer, including patients with ESR1 mutant tumors. Citation Format: Kaklamani VG, Kabos P, Elledge R, Harb W, Purandare D, O'Neill A, Garner F, Bardia A. A phase 1 study of RAD1901, a novel, oral selective estrogen receptor degrader, for the treatment of ER-positive advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-06.

Abstract IA11: Discovery and characterization of potent and selective inhibitors of ATR kinase as anti-cancer agents

Abstract DNA damaging agents, such as cisplatin, gemcitabine or ionizing radiation (IR), represent the cornerstone for the treatment of cancer. However, for many patients they provide only modest benefit. One reason for this is the presence of highly effective cellular processes that detect and repair damaged DNA. The kinase ataxia telangiectasia mutated (ATM) and rad3 related (ATR) is a key mediator for one such cellular repair process that responds to replication stress (RS). RS arises when the DNA replication machinery stalls, leading to production of ssDNA, which directly recruits ATR. This occurs at difficult to replicate sites of the genome, when nucleotides are limiting, or when the replication machinery encounters DNA lesions. RS levels are often elevated in cancer cells, for example due to expression of oncogenes that drive unregulated proliferation, an hypoxic environment, or from treatment with DNA damaging drugs and ionizing radiation (IR). Once recruited to sites of RS ATR mediates activation of cell cycle checkpoints, stabilization of the stalled replication fork and repair of damaged DNA by homologous recombination (HR). Unresolved RS often leads to lethal double strand breaks. Over the past few years a number of potent and selective inhibitors of ATR have been reported and are widely used as pre-clinical tools to assess ATR inhibition as an anti-cancer approach. In vitro, inhibition of ATR potentiates the cytotoxic activity of many DNA damaging drugs and IR in many cancer cell lines. In stark contrast non-cancer cells tolerate inhibition of ATR with just transient and rapidly reversible growth arrest. This ability to tolerate ATR inhibition has been attributed to activation of a compensatory damage response mediated by the ATR homolog ATM. Accordingly, defects in ATM pathway function, for example from loss of expression in ATM or defects in a principle ATM substrate, p53, can confer cell sensitivity to ATR inhibition. In human cancer cell line, and patient-derived tumor, mouse xenografts, ATR inhibition markedly enhances the efficacy of a range of DNA damaging chemotherapies and IR with minimal impact on body weight loss. ATR inhibition has also shown single agent activity in certain cancer cell lines that have high background RS levels from expression of oncogenes such as Ras, defects elsewhere in the DNA repair network (e.g., ERRC1), or reliance on the HR-dependent alternative lengthening of telomeres (ALT) mechanism of telomere maintenance. Finally, ATR inhibition has recently been shown to have benefit when combined with targeted agents that impair other components of the DNA damage response. The best characterized of these are inhibitors of poly ADP-ribose polymerase (PARP), which is involved in the repair of single strand breaks and replication fork dynamics. Three ATR inhibitors are in clinical development, progressing as monotherapy and in combination with DNA damaging drugs and IR. Preliminary evidence of clinical activity has recently been reported for the first-in-class agent VX-970. Citation Format: John R. Pollard. Discovery and characterization of potent and selective inhibitors of ATR kinase as anti-cancer agents. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA11.

Abstract CT014: GSK525762, a selective bromodomain (BRD) and extra terminal protein (BET) inhibitor: results from part 1 of a phase I/II open-label single-agent study in patients with NUT midline carcinoma (NMC) and other cancers

Abstract Background: GSK525762 is a potent, selective pan-BET inhibitor that abrogates binding of BET family proteins (BRD2, BRD3, BRD4 and BRD-T) to acetylated histones. In pre-clinical models this results in suppression of BET target genes that drive oncogenic pathways, resulting in growth inhibition of cancer cell lines (median IC50 of 50-1698 nM for solid tumors and 50 nM for NMC). GSK525762 is being evaluated clinically for treatment of pts with hematologic malignancies and solid tumors including NMC, a rare, aggressive cancer with few treatment options. NMC is characterized by BRD3-/BRD4-NUT fusion oncoproteins that represents a rational therapeutic target for BET inhibitors. Methods: Primary objectives of Part 1 were to determine safety, tolerability, and maximum tolerated dose (MTD) for GSK525762 in solid tumors, using a combined N-CRM and 3+3 dose escalation. Secondary objectives include PK and PD analysis and preliminary evaluation of activity. Oral once daily (qd) and twice daily (bid) schedules have been evaluated. PD activity was assessed with [18F]-deoxy-glucose-PET scans and changes in cytokine release from LPS-stimulated PBMC of treated pts. The dose-limiting toxicity (DLT) observation period was 28 days. Response evaluation was by RECIST 1.1 and pts were followed to disease progression, discontinuation due to adverse events, withdrawal of consent or death. Results: As of 28-Jan 2016, a total of 70 (including 17 NMC) pts have been treated at doses of 2-100 mg qd and 20 and 30 mg bid. The most common adverse events (all grades, ?20%) observed were thrombocytopenia (44%), nausea (40%), vomiting (29%), anemia (26%), fatigue (26%), decreased appetite (24%), diarrhoea (23%) and dysgeusia (20%). DLTs occurred in 5 pts at doses of 60 mg (n = 1, 11%), 80 mg (n = 3, 14%) and 100 mg (n = 1, 11%). The most common AEs leading to dose interruption were thrombocytopenia and hyperbilirubinemia (each n = 7, 10%). Limited data shows similar tolerability at bid doses. PK was dose-proportional after single and repeat dosing with large between patient variability. Dose dependent inhibition of LPS stimulated BRD regulated cytokine (IL-6, TNF-α, MCP-1, IL-8) release suggests target engagement. Of 11 NMC pts treated at 60-100 mg qd, evaluation is awaited on 1 pt. Of 10 pts evaluated, 2 (20%; 95% CI (2.5%, 56%)) had confirmed PR (15 and 23 weeks) and 4 (40%; 95% CI (12%, 74%)) had SD. An 80mg once-daily dose will be evaluated in NMC and other solid tumor expansion cohorts. Conclusion: GSK525762 is an active, orally bio-available BET inhibitor showing dose-proportional PK and good tolerability up to 80 mg qd dosing. Preliminary evidence of clinical activity observed in pts with NMC provides a rational targeted therapy for this aggressive tumor and proof of concept for BET inhibitors in the clinic. Study funded by GSK (NCT01587703). Citation Format: Peter J. O’Dwyer, Sarina A. Piha-Paul, Christopher French, Sara Harward, Gerladine Ferron-Brady, Yuehui Wu, Olena Barbash, Anastasia Wyce, Meg Annan, Thierry Horner, Nigel J. Parr, Rab K. Prinjha, Christopher Carpenter, Geoffrey Shapiro, Arindam Dhar, Christine Hann. GSK525762, a selective bromodomain (BRD) and extra terminal protein (BET) inhibitor: results from part 1 of a phase I/II open-label single-agent study in patients with NUT midline carcinoma (NMC) and other cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT014.

Ramucirumab Clinical Development: an Emerging Role in Gastrointestinal Tumors

Ramucirumab (IMC-1121B, LY3009806) is a fully human G1 monoclonal antibody that specifically targets vascular endotelial growth factor receptor 2 (VEGFR-2) with a substantially greater binding affinity than that of its natural ligands. Early clinical trials in patients with advanced solid tumors demonstrated that biologically relevant blood target concentrations are achievable with tolerable doses, and also showed some preliminary evidence of clinical activity. Several pivotal phase III trials have now been concluded and have led regulatory agencies to grant marketing authorization to ramucirumab for use as second line therapy in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma (as single agent or in combination with paclitaxel), in patients with advanced colorectal carcinoma (CRC) (in combination with infusional fluorouracil and irinotecan (FOLFIRI regimen)) and in patients with advanced non-small cell lung cancer (NSCLC) (in combination with docetaxel). In contrast, ramucirumab failed to significantly improve survival versus placebo as second line therapy in patients with advanced hepatocellular carcinoma (HCC). The aim of this review is to summarize the clinical development and emerging role of ramucirumab in gastrointestinal (GI) tumors, including relevant aspects of its mechanism of action, pharmacology, safety profile, and antitumor activity in gastric, HCC, and CRC carcinomas.

Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia

Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation.Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006).Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented.Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. DisclosuresThomas:Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.

Phase 1 Study of CB-839, a First-in-Class, Orally Administered Small Molecule Inhibitor of Glutaminase in Patients with Relapsed/Refractory Leukemia

Background: Malignant cells alter metabolism in order to enable their highly anabolic state. In addition to a massive increase in glycolysis, neoplastic cells frequently depend on glutamine to feed the TCA cycle and provide key building blocks for cell growth and proliferation. CB-839 is a first-in-class potent and selective inhibitor of the glutaminase (GLS), the first step in glutamine metabolism, and has broad in vitro and in vivo anti-tumor activity in solid and heme malignancies. Acute myeloid leukemia (AML) cells are particularly dependent on glutamine, and treatment of AML cell lines and primary AML cells with CB-839 results in growth arrest and/or cell death (Padre et al., ASH, 2014 and Jacque et al., Blood, 2015). CB-839 causes a decrease in glutamate and glutamate-derived metabolites, such as TCA cycle intermediates and glutathione, crippling the proliferative capacity of these cells and in some cases inducing apoptosis.Methods: CX-839-003 is an ongoing Phase 1 (Ph1) trial of CB-839 in patients with relapsed/refractory hematologic malignancies. This study includes a dose escalation cohort to identify a recommended Phase 2 dose (RP2D), followed by expansion cohorts of patients (pts) with relapsed/refractory AML (IDH wt and mutant), acute lymphocytic leukemia, and IDH-mutant myelodysplastic syndrome (MDS). Pharmacokinetics (PK) is being monitored on Days 1 and 15.Results: Safety data are available for a total of 20 patients (18 AML, 1 ALL, and 1 mixed-lineage leukemia) that have enrolled across the dose escalation and expansion cohorts. These patients have received a median of 3 prior lines of systemic induction therapy, with 5 pts (25%) having received prior allogeneic bone marrow transplantation. Patients' median age was 75 (range 35 to 84). Dose levels from 100-1000 mg TID were explored during the dose escalation. CB-839 has been well tolerated to date, with no DLTs occurring on study. One patient discontinued due to an adverse event (AE) of elevated transaminases, and 5 pts (25%) had G3/4 AEs considered possibly related to study drug. Across three Ph1 studies for CB-839 in solid tumors and heme malignancies, reversible asymptomatic elevations in transaminases have been the primary G3 AE. Although initially CB-839 was given three times daily (TID) without food, the drug is now being given twice daily (BID) with meals based on PK and safety data generated across these 3 studies. Liver abnormalities occurred primarily on the TID schedule in 6/59 (10.2%) pts, but in only one of 60 pts (1.7%) receiving the BID regimen. Pts are currently being enrolled in expansion cohorts at the RP2D, 600 mg BID. Inhibition of GLS activity was evaluated across all 3 Ph1 studies and established clear exposure-dependent inhibition of the target in peripheral blood 4 hr after the first dose of CB-839, with >90% inhibition being maintained for most patients at the RP2D. Preliminary evidence of clinical activity has been noted, including reductions in blast counts in the bone marrow and/or periphery in 2 pts, one of whom achieved a CRi and remains on study for more than one year. 5 (31%) of 16 evaluable pts have remained on study for at least 4 cycles (range 4-17). Additional data from >8 additional patients have recently started on the "BID with meals" regimen will be presented. Correlative studies on clinical samples will also be presented.Conclusions: CB-839 has been well tolerated at and above doses that produced robust inhibition of GLS in blood platelets and in tumors. Dosing BID with food has mitigated the frequency and severity of LFT elevations, which has been the primary safety signal to date. Reductions in marrow and peripheral blast counts in a heavily pretreated acute leukemia population, with a significant number of patients tolerating therapy and remaining on study for a prolonged period, provide the rationale for continued evaluation of CB-839 as a single agent, and in combination with azacitidine, in AML patients. DisclosuresWang:Immunogen: Research Funding. Orford:Calithera Biosciences: Employment, Equity Ownership. Bennett:Calithera Biosciences: Employment, Equity Ownership. Flinn:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

Abstract B27: A phase I dose escalation study of the MDM2 inhibitor DS-3032b in patients with advanced solid tumors and lymphomas

Abstract Background: Reactivation of the tumor suppressor functions of p53 by targeting its negative regulator mdm2 represents an attractive approach to treat cancers expressing wildtype functional p53. DS-3032b disrupts the interaction between p53 and mdm2, and has demonstrated anti-tumor activity preclinically. Here, we report results from the Dose Escalation part (Part 1) of our Phase I Trial in solid tumors and lymphomas which aimed to determine a tentative recommended Phase 2 dose (tRP2D) and characterize the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of DS-3032b. Methods: DS-3032b dose was escalated using an accelerated titration followed by modified Continuous Reassessment Method and Escalation with Overdose Control design, from 15 mg through 30, 60, 120, 160, and 240 mg in a PO QD schedule in 21 of 28 days per cycle (QD 21/28). A 90 mg dose schedule of everyday administration (QD 28/28) had also been tested. Results: Thirty-one of 34 patients (pts) enrolled were evaluable for dose limiting toxicities (DLT). Of the 13 different tumors types enrolled, 77% were TP53 wildtype, with well-differentiated/de-differentiated (WD/DD) liposarcoma (LPS) being the most frequent (n = 13; 44%). The maximum tolerated dose (MTD) was determined to be 120 mg with 2/13 DLTs for the QD 21/28 schedule, which is currently being evaluated as the tRP2D in the Dose Expansion part (Part 2) of the study in more limited tumor types. The MTD was 90 mg with 1/9 DLT for the QD 28/28 schedule. The most common drug-related adverse events (AEs) were hematological (thrombocytopenia (Th) [68%], anemia [35%], neutropenia [29%] gastrointestinal (nausea [71%], vomiting [32%] and diarrhea [38%]), and fatigue [47%]. Prolonged Th resulting in >4 weeks dose interruption was seen in 8 pts, 2 were treated at the tRP2D. Bone marrow examination performed in selected pts revealed no dysplastic changes. A total of 6 pts experienced DLTs, all treated at MTD or higher. The 3 MTD DLTs were caused by Th that resulted in >1 week delay in starting Cycle 2. There was a moderate degree of inter-patient variability in PK exposure, with considerable overlap in exposures at the two MTDs (Cycle 1 Day 1 mean Cmax = 559.9 and 567.7 ng/mL, and mean AUC 0-24 = 8047.7 and 8629.3 ng*h/mL respectively for 120 and 90 mg doses). The steady state Cmin at MTDs exceeded the levels demonstrated as necessary for both disrupting MDM2-p53 interactions and showing antitumor activity preclinically. Induction of the PD biomarker MIC 1 in serum correlated with drug exposure. Twenty three pts were evaluable for tumor response. Most pts (20/26) experienced stable disease (SD) as the best tumor response though no pt had an objective response. The median progression free survival (mPFS) for all evaluable pts at 5.7 months, with 3 (1 carcinoid and 2 liposarcoma; all contain MDM2 amplification) still on study after receiving therapy for 12+, 20+, and 21+ cycles. The greatest tumor shrinkage and most durable SD were seen in pts with WD/DD LPS with mPFS of 6.3 months and 3-month PFS rate of 92%. Conclusions: DS-3032b shows an acceptable safety profile at the tRP2D of 120mg QD x 21/28. Preliminary evidence of clinical activity with prolonged PFS was seen in WD/DD LPS in which MDM2 is universally amplified, warranting further investigation in this disease. ClinicalTrials.gov Identifier: NCT01877382 Citation Format: Todd Bauer, David Hong, Neeta Somaiah, Charles Cai, Saeheum Song, Prasanna Kumar, Roohi Gajee, Michael Rosen, Jarema Kochan, Shuquan Chen, David Hyman, Tyler Masters, Funda Meric-Bernstam, Archie Tse, Patricia LoRusso, Amy Weise, Mrinal Gounder. A phase I dose escalation study of the MDM2 inhibitor DS-3032b in patients with advanced solid tumors and lymphomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B27.

Abstract 3400A: Development and application of an immunohistochemistry-based clinical assay for evaluating Folate Receptor Alpha (FRα) expression in a phase I clinical trial of IMGN853

Abstract A biomarker-based patient selection strategy, coupled with the co-development of a companion diagnostic, is key to the successful development of molecularly targeted cancer therapeutics. IMGN853 is a Folate Receptor Alpha (FRα)-targeting antibody-drug conjugate (ADC) consisting of an anti-FRα antibody linked to DM4, a highly cytotoxic maytansinoid, via a cleavable disulfide linker. FRα is a glycosyl-phosphatidylinositol-linked membrane protein commonly over-expressed in several solid tumor types including epithelial ovarian cancer (EOC), endometrial cancer and lung adenocarcinoma, with limited expression in normal tissues. Previously reported preclinical data demonstrated regression or significant inhibition of tumor growth by the conjugate in tumor models with clinically relevant levels of FRα expression. IMGN853 is currently in a phase I clinical trial for safety and tolerability in patients with FRα-positive solid tumors. Preliminary evidence of clinical activity has been observed in patients receiving IMGN853 treatment. Immunohistochemistry (IHC) is one of the most widely adopted techniques in clinical labs for semi-quantitative determination of protein expression in different cellular compartments. We have developed an IHC assay to support the FRα-expression based patient selection strategy in the clinical development of IMGN853. To this end, a novel murine monoclonal antibody with high specificity for human FRα was generated. This antibody, 353-2.1, is compatible with formalin fixed and paraffin embedded (FFPE) tissue samples and can recognize the same pool of FRα molecules as IMGN853, making it an ideal candidate for a companion diagnostic for IMGN853. The antibody was used to develop and optimize an assay that covers a broad dynamic range of FRα expression, allowing discrimination among high, moderate and low levels of expression. Data from tissue microarrays that cover a broad range of normal and tumor tissue types, as well as additional prevalence data in selected tumor types, were used to validate this assay. They also demonstrate that the FRα-expression data generated using this assay are consistent with previous findings. This clinical FRα IHC assay has been successfully used to measure FRα expression in more than 100 patient tumor samples submitted for testing in the ongoing IMGN853 phase I trial. A summary of FRα staining pattern and expression level data from these patients will be presented, as well as the prevalence in each tumor type. Citation Format: Jianhua Zhao, Alyssa LaBelle, Olga Ab, Krista Acosta, Al Yates, Yinghui Zhou, Angela Romanelli. Development and application of an immunohistochemistry-based clinical assay for evaluating Folate Receptor Alpha (FRα) expression in a phase I clinical trial of IMGN853. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3400A. doi:10.1158/1538-7445.AM2015-3400A

Phase I dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumours

BackgroundOrally administered SNX-5422, a novel, selective prodrug of the Heat shock protein 90 (Hsp90) inhibitor SNX-2112, was investigated in two sequential phase I studies to determine the safety, maximum tolerated doses (MTDs) and pharmacokinetic profile of SNX-5422. MethodsUsing a dose-escalation design, 3–6 adults with advanced solid tumours received SNX-5422 every-other-day (QOD) or once-daily (QD) 3weeks on/1week off or QD continuously, with disease assessments every 8weeks. Single-dose and steady-state pharmacokinetic parameters of SNX-2112 were determined. ResultsIn total, 56 patients were enrolled: QOD 3weeks on/1week off, n=36; QD 3weeks on/1week off, n=17; QD continuous, n=3. Doses ranged from 4 to 133mg/m2 QOD and 50 to 89mg/m2 QD. The MTDs were defined as 100mg/m2 QOD and 67mg/m2 QD, respectively, with diarrhoea being dose-limiting on both 3weeks on/1week off schedules. Overall, treatment-related adverse events were mainly low grade, including diarrhoea (64%), nausea (39%), fatigue (28%), and vomiting (28%). Reversible grade 1–3 nyctalopia (night blindness) was reported by four patients (dose: 50–89mg/m2 QD; 100mg/m2 QOD). Exposure was generally linear, though greater than dose-proportional. Of 32 evaluable patients on QOD dosing, there was one durable complete response (prostate cancer), one confirmed (HER2+breast cancer) and one unconfirmed partial response (adrenal gland cancer). Three patients (QOD schedule) had stable disease for ⩾6months. ConclusionsThe dose and schedule recommended for further study with SNX-5422 is 100mg/m2 QOD 3weeks on/1week off based on improved tolerability and preliminary evidence of clinical activity.

Phase 1/2 study of KRN330, a fully human anti-A33 monoclonal antibody, plus irinotecan as second-line treatment for patients with metastatic colorectal cancer

KRN330 is a recombinant, fully-human monoclonal antibody directed against A33, a surface differentiation antigen that is uniformly expressed in 95% of colorectal cancers. A previous Phase 1 study of single-agent KRN330 identified a maximum tolerated dose (MTD) of 3mg/kg q2w and preliminary evidence of clinical activity among patients with advanced and metastatic colorectal cancer (mCRC). This Phase 1/2 trial sought to assess the safety and activity of second-line KRN330 plus irinotecan in patients with mCRC. Patients with mCRC who showed disease progression after FOLFOX/CapOx received intravenous doses of KRN330 (0.5 or 1.0mg/kg qw or q2w) plus irinotecan (180mg/m(2)) in a standard 3 + 3 dose escalation. The MTD of KRN330 with irinotecan in 19 patients was 0.5mg/kg qw in the Phase 1 study with gastrointestinal effects and neutropenia being the predominant dose-limiting toxicities. In the Phase 2 study, the most frequent treatment-related Grade ≥3 toxicities in 44 patients were fatigue (15.9%), neutropenia (13.6%), leukopenia (6.8%), diarrhea (4.5%), and dehydration (4.5%). Objective response rate (ORR) was 4.5% and disease control rate was 45.5% for the intent-to-treat population. Median progression-free survival was 87days (95% CI, 43-136days). The prespecified ORR of KRN330 plus irinotecan was not met. Further investigation of KRN330 plus other agents may be warranted.

Phase I trial combining temozolomide plus lapatinib for the treatment of brain metastases in patients with HER2-positive metastatic breast cancer: the LAPTEM trial

BackgroundBrain metastases (BMs) pose a clinical challenge in breast cancer (BC). Lapatinib or temozolomide showed activity in BM. Our study assessed the combination of both drugs as treatment for patients with HER2-positive BC and BM. MethodsEighteen patients were enrolled, with sixteen of them having recurrent or progressive BM. Any type of previous therapy was allowed, and disease was assessed by gadolinium (Gd)-enhanced magnetic resonance imaging (MRI). The primary end points were the evaluation of the dose-limiting toxicities (DLTs) and the determination of the maximum-tolerated dose (MTD). The secondary end points included objective response rate, clinical benefit and duration of response. ResultsThe lapatinib–temozolomide regimen showed a favorable toxicity profile because the MTD could not be reached. The most common adverse events (AEs) were fatigue, diarrhea and constipation. Disease stabilization was achieved in 10 out of 15 assessable patients. The estimated median survival time for the 16 patients with BM reached 10.94 months (95% CI: 1.09–20.79), whereas the median progression-free survival time was 2.60 months [95% confidence interval (CI): 1.82–3.37]. ConclusionsThe lapatinib–temozolomide combination is well tolerated. Preliminary evidence of clinical activity was observed in a heavily pretreated population, as indicated by the volumetric reductions occurring in brain lesions.

Abstract B79: A first-in-human Phase 1 study of anti-cancer stem cell (CSC) agent OMP-54F28 (FZD8-Fc) targeting the WNT pathway in patients with advanced solid tumors.

Abstract Introduction: OMP-54F28 is a first-in-class recombinant fusion protein of the extracellular domain of the human frizzled (FZD) 8 receptor and a human IgG1 Fc fragment. OMP-54F28 binds Wnt ligands and thereby blocks signaling of the WNT/FZD signaling pathway, a key oncologic pathway in numerous tumor types that is implicated in tumor cell de-differentiation and cancer stem cell (CSC) function. In patient-derived xenograft models, OMP-54F28 inhibits growth of several tumor types (such as pancreatic, ovarian, hepatocellular, colorectal, and breast), reduces CSC frequency, promotes differentiation of tumor cells, and synergizes with chemotherapy. Methods: The objectives of this study are to determine the maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of OMP-54F28 as a single agent. A 3+3 design was used, and OMP-54F28 was given intravenously every 3 weeks. Results: 17 patients have been treated in 5 dose-escalation cohorts (0.5, 1, 2.5, 5 and 10 mg/kg). The most common related Grade 1 and 2 adverse events (AEs; >10% of patients) were decreased appetite, fatigue, hypocalcemia, nausea, dysgeusia, increased blood pressure, peripheral edema and vomiting. The only related Grade ≥3 AE was Grade 3 anemia in one patient at the 2.5 mg/kg dose level. OMP-54F28 clearance was dose-dependent, consistent with target-mediated drug disposition, with a half-life of approximately 4 days at 10 mg/kg. Exposure at the current highest dose level approximates the exposure in nonclinical models where optimal efficacy was observed. Two patients demonstrated doubling from baseline of β-C-terminal telopeptide (β-CTX), a marker of increased bone turnover, consistent with PD modulation of the WNT pathway in bone by OMP-54F28. One of these patients received zoledronic acid as per protocol (2nd patient declined), and β-CTX returned to baseline. Additional PD biomarker analyses are ongoing in hair follicles, blood cells and paired tumor biopsies. Best tumor response observed was stable disease in three patients (pancreatic cancer, renal cell carcinoma and desmoid tumor) for approximately 3, 3 and 2+ months, respectively. Conclusions: OMP-54F28 is well tolerated through 10 mg/kg. Dose escalation continues, and updated clinical, PK, and PD data will be presented. Bone biomarker data are consistent with modulation of the WNT pathway, and preliminary evidence of clinical activity has been noted in several patients. Three Phase 1b studies in solid tumor indications are being initiated to study OMP-54F28 in combination with chemotherapy and/or targeted agents. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B79. Citation Format: David C. Smith, Michael Gordon, Wells Messersmith, Rashmi Chugh, David Mendelson, Jakob Dupont, Robert Stagg, Ann M. Kapoun, Lu Xu, Rainer K. Brachmann, Antonio Jimeno. A first-in-human Phase 1 study of anti-cancer stem cell (CSC) agent OMP-54F28 (FZD8-Fc) targeting the WNT pathway in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B79.

A phase I study of lirilumab (BMS-986015), an anti-KIR monoclonal antibody, administered in combination with ipilimumab, an anti-CTLA4 monoclonal antibody, in patients (Pts) with select advanced solid tumors.

TPS3106 Background: Immune checkpoint blockade represents a novel form of cancer immunotherapy. Killer cell immunoglobulin-like receptors (KIR) and cytotoxic T lymphocyte antigen-4 (CTLA-4) are immune receptors that down-regulate NK and T cell activity, respectively. The anti-KIR antibody, lirilumab (BMSE986015), potentiates innate immunity by blocking signaling through inhibitory KIRs and has demonstrated modest side effects in a Phase I trial. The anti-CTLA-4 antibody, ipilimumab, potentiates adaptive immunity and has demonstrated improved overall survival in pts with advanced melanoma and preliminary evidence of clinical activity in Phase I and II trials. We hypothesized that coordinate modulation of innate and adaptive immunity by combining anti-KIR and anti-CTLA4 antibodies could achieve enhanced biologic and clinical activity compared to either agent alone. Here, we describe a Phase I study of lirilumab plus ipilimumab in pts with selected advanced solid tumors. Methods: This study will be performed in two parts and enroll approximately 150 pts. During dose escalation, pts with advanced melanoma, non-small cell lung cancer and castrate resistant prostate cancer, will be enrolled. During cohort expansion, 20 pts with each tumor type will be enrolled at the maximum tolerated dose (MTD), or the maximum administered dose, if no MTD is defined. The primary study objectives are to delineate the safety and tolerability, dose limiting toxicities, and MTD of this combination. Secondary objectives are to assess preliminary anti-tumor activity, pharmacokinetics, and immunogenicity of this combination in all pts, and the pharmacodynamic effects on tumor infiltrating lymphocytes in a cohort of melanoma pts. Exploratory objectives include a thorough assessment of the modulation of innate and adaptive immunity by this combination in peripheral blood and/or tumor specimens, and preliminary evaluation of the association of these changes with clinical outcome. Clinical trial registration number: NCT01750580 Clinical trial information: NCT01750580.

Phase I Trial of Intravesical Recombinant Adenovirus Mediated Interferon-α2b Formulated in Syn3 for Bacillus Calmette-Guérin Failures in Nonmuscle Invasive Bladder Cancer

A phase I trial of intravesical recombinant adenovirus mediated interferon-α2b gene therapy (rAd-IFNα) formulated with the excipient SCH Syn3 was conducted in patients with nonmuscle invasive bladder cancer who had disease recurrence after treatment with bacillus Calmette-Guérin. The primary objective was to determine the safety of rAd-IFNα/Syn3. Secondary end points were demonstrated effective rAd-IFNα gene expression and preliminary evidence of clinical activity at 3 months. A total of 17 patients with recurrent nonmuscle invasive bladder cancer after bacillus Calmette-Guérin treatment were enrolled in the study. A single treatment of rAd-IFNα (3 × 10(9) to 3 × 10(11) particles per ml) formulated with the excipient Syn3 was administered. Patient safety was evaluated for 12 or more weeks. Efficacy of gene transfer was determined by urine IFNα protein concentrations. Preliminary drug efficacy was determined at 3 months. Intravesical rAd-IFNα/Syn3 was well tolerated as no dose limiting toxicity was encountered. Urgency was the most common adverse event and all cases were grade 1 or 2. rAd-IFNα DNA was not detected in the blood. However, transient low serum IFNα and Syn3 levels were measured. High and prolonged dose related urine IFNα levels were achieved with the initial treatment. Of the 14 patients treated at doses of 10(10) or more particles per ml with detectable urine IFNα, 6 (43%) experienced a complete response at 3 months and 2 remained disease-free at 29.0 and 39.2 months, respectively. Intravesical rAd-IFNα/Syn3 was well tolerated with no dose limiting toxicity encountered. Dose dependent urinary IFNα concentrations confirmed efficient gene transfer and expression. Intravesical rAd-IFNα/Syn3 demonstrated clinical activity in nonmuscle invasive bladder cancer recurring after bacillus Calmette-Guérin.