Expansion Cohort Of Patients Research Articles

Abstract CT143: Phase I study of the combination of a RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers

Abstract Background: Preclinical experiments in-vitro show MEK inhibitors can cause upregulation of p-FAK in KRASM cells. The combination of a MEK and FAK inhibitor could overcome this in-vitro and in-vivo. Methods: We are conducting an open label phase I dose escalation with expansion study (NCT03875820). Dose escalation evaluated a twice a week schedule (Mon/Thurs) CH5126766/VS-6766 (CH) 3 weeks out of 4 with a twice a day dosing schedule of defactinib (Def) administered 3 weeks out of 4. The dose levels explored were cohort 1 (CH 3.2 mg, 200 mg Def), cohort 2a (CH 4 mg Def 200 mg) and cohort 2b (CH 3.2 mg and Def 400 mg). Pharmacokinetic data were collected at cycle 1 d15 when both drugs were administered. In a subset of patients consenting to multiple biopsies, 3 biopsies were performed (baseline, after a single dose of CH run in and after 8-15 days of the combination therapy). At the recommended phase 2 dose (R2PD), expansion cohorts in patients with low grade ovarian cancer (LGSOC, n=20), KRASM non-small cell lung cancer (NSCLC, n=20) and KRASM colorectal cancer (CRC, n=10) will be treated. Results: Forty two patients have been treated on the trial so far. There were no dose limiting toxicities (DLTs) in the first 3 patients in cohort 1 and thus patients were recruited to cohort 2a and 2b. The cohort 2b dose level was deemed intolerable because of 2/3 patients experiencing DLTs of grade 2 rash not allowing dosing of 75% of the planned dose. No DLTs were seen in the first 6 patients treated on schedule 2a. However, given chronic grade 2 toxicities in patients on treatment > 6 months, the RP2D was deemed to be cohort 1. The most common side effects in the study were rash, CK elevation, AST elevation, hyperbilirubinemia and nausea, most of which were NCI CTC grade 1-2. All changes were reversible. The mean AUC of CH and Def at R2PD was 6179 ng*hr/ml and 2071 ng*hr/ml, respectively, which is in the range of what was seen in the single agent dose escalation studies. Sequential biopsies were obtained in 7 patients and 6/7 showed an increase in p-FAK following single agent CH which was reduced in 5/7 with combined CH and Def therapy. The response rate was 67% (4/6) or 50% (4/8) in KRASM LGSOC or all LGSOC patients treated to date, respectively. A range of KRASM were found in tumors of LGSOC patients who responded (G12V, G12A and G12D). Of the 4 patients with LGSOC who have responded to treatment, 3 have had a prior MEK inhibitor and are currently are on study for a median of 20.5 months (range 7-23 months). Expansion cohorts in LGSOC and KRASM NSCLC and CRC are ongoing and will be presented. Conclusion: We report a novel intermittent schedule of the combination of a RAF-MEK and FAK inhibitor with very promising clinical activity in patients with KRASM LGSOC including those who had been previously treated with a MEK inhibitor. Citation Format: Rajiv Shinde, Angelika Terbuch, Martin Little, Reece Caldwell, Roopa Kurup, Ruth Riisnaes, Mateus Crespo, Ruth Ruddle, Bora Gurel, Adam Stewart, Jenny King, Mona Parmar, Alison Turner, Florence Raynaud, Muneeb Mahmud, Christina Yap, Jonathan A. Pachter, Gordon B. Mills, Anna Minchom, Juanita Lopez, Susana N. Banerjee, Johann S. de Bono, Matthew Krebs, Udai Banerji. Phase I study of the combination of a RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT143.

Abstract 561: Preclinical efficacy data for the anti-CEACAM5-DM4 ADC SAR408701 supports further development in lung and gastro-intestinal cancers

Abstract Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a cell-surface glycoprotein highly expressed in several tumor types including non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and gastric cancer (GC). SAR408701 is an antibody-drug conjugate (ADC) which consists of anti-CEACAM5 antibody conjugated to the maytansinoid DM4 cytotoxic agent, a highly potent tubulin inhibitor. SAR408701 was investigated in a First in Human trial (FIH) in patients with advanced solid tumors. During the early dose escalation phase, preliminary anti-tumor activity was observed with objective response reported in 3 patients with CRC and 1 patient with GC. In an interim analysis of an ongoing expansion cohort of patients with non-squamous NSCLC and with CEACAM5 expression in ≥ 50% of tumor cells, 25% overall response rate (ORR) (8/32 evaluable patients) and 37.5% (12 patients) stable disease were observed. In parallel to FIH trial, several preclinical studies were performed to support the clinical development of SAR408701 in NSCLC, CRC and GC. A single mouse trial (SMT) was carried out on a panel of 28 patent-derived xenografts (PDX) covering the top 3 indications. The SMT format employs a single mouse per PDX model and treatment arm and uses RECIST criteria as readout. Results showed an efficacy profile in the preclinical trial close to that obtained in clinic with an ORR of 10% in CRC, of 50% in lung cancers and of 37.5% in GC. The efficacy of SAR408701 is correlated with CEACAM5 expression in lung and gastric indications. To further assess the potential of SAR408701 in NSCLC, preclinical investigations have been done to determine if an ADC-DM4 could be beneficially combined with immune checkpoint inhibitors (ICIs). The capacity of DM4-treated tumor cells to immunize immune competent mice to the tumor was evaluated, indicating that DM4 can induce immunogenic cell death. This result supports the development of SAR408701 in combination with ICIs in NSCLC. The combination of SAR408701 with 4 different standard of care (SoC) therapies were tested in 2 CRC PDX models, one sensitive and one resistant to SAR408701 alone. Combinations of SAR408701 were evaluated with either FOLFOX regimen, FOLFIRI regimen, TAS-102 or cetuximab. All combinations resulted in significantly better antitumor activity than single agent arms in both resistant and sensitive PDXs without an increase in toxicity and showed a therapeutic synergy. These results suggest that SAR408701 can be advantageously combined with SoC in gastro-intestinal (GI) cancers. In summary, preclinical data show that SAR408701 displays a strong antitumor activity as a single agent in NSCLC and in combination with SOC in GI cancers, supporting further development in these indications. Furthermore, SAR408701 could be a potential good candidate to be combined with ICIs in NSCLC. Citation Format: Stephanie Decary, Olivier Lemaitre, Anne-Marie Lefebvre, Alexandra Ferrier, Marielle Chiron, Dmitri Wiederschain, Anne-Sophie Lacoste-Bourgeacq, Nathalie Le Bail, Sukhvinder Sidhu, Cecile Combeau, Mustapha Chadjaa, Celine Nicolazzi. Preclinical efficacy data for the anti-CEACAM5-DM4 ADC SAR408701 supports further development in lung and gastro-intestinal cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 561.

A phase I trial a FR alpha targeted thymidylate synthase inhibitor CT900 exploring four schedules of treatment in expansion cohorts of patients with high-grade serous ovarian cancer.

6043 Background: CT900 (BTG945/ONX-0801) is a novel small molecule that binds to folate receptor alpha (FRα), is internalized and causes cytotoxicity by thymidylate synthase inhibition. Methods: The aims of the expansion cohorts were to determine toxicity, response rates and correlation of the response to FRα expression in patients with HGSOC (NCT02360345). Four expansion cohorts were studied which included: schedule A (6 mg/m2/q every 2 weeks), schedule B (12 mg/m2/q every 2 weeks), schedule C (12 mg/m2/q every 2 weeks with 12 mg dexamethasone IV and 8 mg of dexamethasone for 2 days) and schedule D (12 mg/m2/q every 3 weeks). Response rates were assessed by RECIST V1.1 and GCIG CA125 response criteria. Patients who were withdrawn for reasons other than toxicity within 8 weeks (cohorts A, B, C) and 12 weeks (cohort D) were not assessable for efficacy. FRα expression was quantified using immunohistochemistry. Results: A total of 67 patients were treated in the 4 cohorts (14, 25, 15 and 13 for cohorts A, B, C and D). The median age was 62 (IQR 57 - 68) and the median lines of previous treatment was 5 (range 1 to 13). A majority of patients were platinum resistant. The most common toxicities across all expansion cohorts were: fatigue (51%), nausea (36%), anemia (27%), fever (25%), AST elevation (21%), most of which were grade 1 - 2. Toxicity of special interest included radiological changes of pneumonitis and was 15% in all cohorts (7%, 16%, 27% and 8% in cohorts A, B, C and D, respectively). These changes were grade 1 - 2 in all but one case. RECIST response rates in evaluable patients across the different cohorts were: A 1/8 (13%), B 6/21 (29%), C 5/12 (42%) and D 2/12 (17%). FRα expression in archival tumor tissue was measured in 59/67 patients. Expression was found to be high/medium in 43/59 (73%), low in 7/59 (12%) and negative/very low in 9/59 (15%). In patients with high/medium FRα expression, the RECIST response rates in different cohorts were: A 0/9 (0%), B 6/16 (38%), C 4/12 (33%) and D 1/6 (17%). The CA125 response rate in all patients within cohort B was 13/25 (52%) and 10/16 (63%) in patients with high/medium FRα expression. Conclusions: CT900 has shown clinical activity in patients with heavily pre-treated platinum-resistant, high/medium FRα expressing HGSOC. Based on toxicity and efficacy, the schedule of 12 mg/m2/q2 weekly (schedule B) is the recommended phase II dose for further evaluation in patients with relapsed high/medium FRα expressing HGSOC. Clinical trial information: NCT02360345.

First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody–Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors

PURPOSEThis phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody–drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin.PATIENTS AND METHODSThis phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week.RESULTSForty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non–small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity.CONCLUSIONAnetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.

Phase I dose-escalation trial of trifluridine/tipiracil (TAS-102) and temozolomide in the treatment of advanced neuroendocrine tumors.

615 Background: Systemic chemotherapy plays a role in treating neuroendocrine tumors. Trifluridine/tipiracil (FTD/TPI), known as TAS-102, is an antineoplastic agent that is non-cross resistant with 5-fluorouracil and capecitabine and that has a different toxicity profile. We are presenting results from a phase 1 portion of the study evaluating safety of FTD/TPI in combination with TMZ in patients in neuroendocrine tumors. Methods: Phase 1 portion to the study utilized “3+3” design to determine maximum tolerated doses (MTD) of FTD/TPI and TMZ when administered in combination. Patients with advanced NETs of any grade were eligible for participation. FTD/TPI was taken twice a day on days 1-5 and 8-12 and TMZ was taken daily on days 8-12 of a 28 day cycle. 3 dose levels (Lv) were evaluated. FTD/TPI was started at a goal dose of 35 mg/m2 twice daily. Three doses of TMZ were studied: 100, 150 and 200 mg/m2. Growth factor support was required during DLT evaluation period for all patients starting with the fourth subject on study. Results: Sixteen evaluable subjects (6 females, median age 64) enrolled in the phase 1 portion of the study (4 on Lv1, 6 on Lv2, 6 on Lv3). 3/16 had high-grade tumors, 8/16 had non-GI or unknown primary. No DLTs were observed on Lv1. One DLT was observed on Lv2 (grade 3 fatigue and inability to resume treatment) and 1 DLT on Lv3 (grade 4 thrombocytopenia). Overall the treatment was well tolerated. 7 subjects had grade ≥3 AEs at least possibly related to treatment, with neutropenia and lymphopenia being the most common. 4 subjects required dose reductions. 7 subjects remain on active treatment. 4 subjects discontinued treatment due to AEs and 1 due to clinical disease progression. Efficacy data is being collected and will be presented at the meeting. Conclusions: This study established MTD of FTD/TPI (35mg/m2 twice daily) and TMZ (200 mg/m2). This regimen is well tolerated. Enrollment into expansion cohort for patients with advanced Grade 1-2 pancreatic NETs is ongoing (NCT02943733). Clinical trial information: NCT02943733.

Abstract CT056: A Phase Ia/IIa trial of AVID100, an anti-EGFR antibody-drug conjugate

Abstract Background AVID100, a rationally designed anti-EGFR-DM1 conjugate, showed potent activity in preclinical models, including cancer cell lines resistant to approved anti-EGFR monoclonal antibodies. In addition, AVID100 showed increased toxicity on tumor cells compared to the unconjugated antibody. There was no increased AVID100-mediated toxicity on keratinocytes. Methods In the completed Phase Ia segment, 24 patients with advanced or metastatic epithelial malignancies without available standard of care therapy and likely to express EGFR were enrolled into sequential dose-escalation cohorts to assess safety, tolerability, pharmacokinetic (PK) parameters, and to identify the recommended Phase II dose (R2PD) of 2 hour infusions on an every 3 week schedule. In the ongoing Phase IIa segment, preliminary antitumor activity is being assessed in expansion cohorts of patients with high EGFR expression, including triple-negative breast cancer (TNBC) (2+ expression in ≥75% or 3+ in ≥50% of tumor cells) or either squamous cell carcinoma of the head and neck (SCCHN) or squamous non-small cell lung carcinoma (sqNSCLC) (3+ expression in ≥ 50% of tumor cells). The DAKO PharmDx assay was validated and used for screening intensity of EGFR protein expression. Results During Phase Ia, no Cycle 1 dose limiting toxicities (DLTs) were observed in Cohorts 1-6 at doses (N) of 20 (1), 40 (1), 80 (3), 120 (3), 180 (3), and 220 (6) mg/m2. In Cohort 7 (6) (270 mg/m2; ~ 7.3 mg/kg) two patients experienced Cycle 1 DLTs (G3 asymptomatic lipase elevation, G4 reversible thrombocytopenia), exceeding the maximally tolerated dose. A third patient developed G3 reversible pneumonitis. As a result, 220 mg/m2 (~6 mg/kg) was selected as the R2PD. Tumor types in greater than one patient included: colorectal (13), breast (4), and ovarian (2). Preliminary PK results at the R2PD revealed exposure exceeding preclinically predicted therapeutic levels. Cmax increased proportionally with dose, plasma half-life was ~50 hours at the R2PD, and clearance decreased with increasing doses with saturation observed between 180-270 mg/m2. Safety and tolerability were acceptable. Other treatment-related adverse events included: infusion-related reactions that were ameliorated by premedication and infusion prolongation, rash, nausea, vomiting, fatigue, headache, anorexia, mucositis, punctate keratitis, diarrhea, elevated amylase, reversible transaminase and alkaline phosphatase elevations without other evidence of hepatotoxicity, hypomagnesemia, and hypokalemia. Prolonged disease stabilization was observed in 3 of these patients not selected for EGFR overexpression (colorectal, ovarian, cervical). Conclusions AVID100 is a well-tolerated anti-EGFR-DM1 conjugate with evidence for exposure levels at or above those observed for cetuximab and ado-trastuzumab emtansine. Antitumor activity is currently being evaluated in EGFR-overexpressing patients in Phase IIa. Citation Format: Nehal Lakhani, Sreenivasa Chandana, Anthony Tolcher, Yvette Cole, Karla Rivas, Sandra Sinclair, Paul I. Nadler, Debra L. Wood, Kyri P. Papadopoulos. A Phase Ia/IIa trial of AVID100, an anti-EGFR antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT056.

Abstract 4074: Heat shock protein 90 inhibitors alter pancreatic stellate cell cytokine production and enhances the efficacy of immune checkpoint blockade in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC). Prior work from our laboratory has defined a role for stroma-derived cytokines such as IL-6 as a significant barrier restraining immunity against PDAC. Our group is pursuing novel approaches to target pathways in the tumor microenvironment (TME), in an effort to improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90), is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC has not been explored in detail. We hypothesize that targeting Hsp90 can modulate the TME, through its ability to target inflammatory signaling and cytokine production by PSC and enhance the efficacy of immunotherapy. Treatment of immortalized and primary patient PSC with the Hsp90 inhibitor XL888 led to decreased IL-6 at the transcript and protein level in vitro. XL888 directly limited PSC growth, and reduced expression of alpha-SMA, Jak/STAT and MAPK signaling intermediates as determined via immunoblot. Combined therapy with XL888 and anti-PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC-Luc) tumors, as compared to treatment with either agent alone. The treatment was well-tolerated, with no difference in body weight observed in either model. Laboratory studies are assessing immune and stromal biomarkers to define the impact on PSC, cytokines and T-cell biomarkers in the TME. Finally, we have completed the dose escalation phase of a Phase Ib/II clinical trial of XL888 (Hsp90i) and pembrolizumab (anti-PD-1) at our institution. Expansion cohorts of patients with metastatic pancreatic cancer (n=16) or colorectal cancer (n=16) are now accruing, with paired biopsy and peripheral blood samples to address the impact of Hsp90 inhibition on anti-PD-1 mediated T cell proliferation, cytokine production, and PSC-derived cytokine signatures. Citation Format: Mohammad Zaidi, Yuchen Zhang, Michael B. Ware, Matthew R. Farren, Hannah Komar, Brian Olson, Ganji P. Nagaraju, Mehmet Akce, Olatunji Alese, Shishir Maithel, Juan Sarmiento, Walid Shaib, Christina Wu, Bassel El-Rayes, Gregory B. Lesinski. Heat shock protein 90 inhibitors alter pancreatic stellate cell cytokine production and enhances the efficacy of immune checkpoint blockade in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4074.

A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas

BackgroundAnaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in non-small-cell lung cancer (NSCLC). TSR-011 is a dual ALK and tropomyosin-related kinase (TRK) inhibitor, active against ALK inhibitor resistant tumours in preclinical studies. Here, we report the safety, tolerability and recommended phase 2 dose (RP2D) of TSR-011 in patients with relapsed or refractory ALK- and TRK-positive advanced cancers.MethodsIn this sequential, open-label, phase 1 trial (NCT02048488), patients received doses of 30 mg, escalated to 480 mg every 24 hours (Q24h), followed by an expansion cohort of patients with ALK-positive cancers. The primary objective was to evaluate safety and tolerability. Secondary objectives included pharmacokinetics.ResultsTSR-011 320- and 480-mg Q24h doses exceeded the maximum tolerated dose. At the RP2D of 40 mg every 8 hours (Q8h), the most common grade 3–4 treatment-emergent adverse events occurred in 3.2–6.5% of patients. Of 14 ALK inhibitor-naive patients with ALK-positive NSCLC, 6 experienced partial responses and 8 had stable disease.ConclusionsAt the RP2D (40 mg Q8h), TSR-011 demonstrated a favourable safety profile with acceptable QTc changes. Limited clinical activity was observed. Based on the competitive ALK inhibitor landscape and benefit/risk considerations, further TSR-011 development was discontinued.Clinical trial registration numberNCT02048488.

A phase I study of BOS172738 in patients with advanced solid tumors with RET gene alterations including non-small cell lung cancer and medullary thyroid cancer.

TPS3162 Background: RET gene alterations (mutations and fusions) leading to constitutive kinase activity have been identified in various tumor types including non-small cell lung cancer (NSCLC), medullary thyroid (MTC), colon, breast and ovarian cancer. The current generation of multi-kinase inhibitors approved for treatment of such tumors, do not selectively target RET and exhibit significant off-target activity especially against vascular endothelial growth factor receptor 2 (VEGFR2), resulting in dose-limiting toxicities that prevent the full inhibition of RET in those tumors. Recently, early clinical data from a class of more selective RET inhibitors have shown promising results with a more favorable safety profile in patients with RET alterations. BOS172738 is a novel RET inhibitor with nanomolar potency against RET and approximately 300-fold selectivity against VEGFR2. This phase 1 study is assessing the safety and tolerability of BOS172738 in patients with advanced solid tumors with RET alterations. Methods: NCT03780517 is a phase 1, open label, multicenter, dose escalation trial to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of BOS172738, an orally dosed RET kinase inhibitor, in patients with advanced solid tumors with RET gene alterations. RET gene alteration status will be assessed locally but confirmed centrally. The study is comprised of 2 parts: in Part A (dose escalation), patients with advanced solid tumors with RET gene alterations will receive BOS172738 orally once daily in each 28-day cycle. Select patients in Part A are eligible for intrapatient dose escalation. On establishing the recommended phase 2 dose (RP2D), Part B (expansion) will enroll up to an additional 60 patients to 1 of 3 tumor type-specific cohorts. The 3 expansion cohorts will each consist of up to 20 advanced cancer patients with: 1) RET gene-fusion NSCLC; 2) RET gene-mutant MTC; and 3) other RET gene-altered advanced tumors or NSCLC/MTC with prior specific RET gene-targeted therapy. Patients in expansion cohorts will receive BOS172738 daily at the RP2D until disease progression or other discontinuation criteria have been met. The study is currently open to enrollment globally with the first patient entered in 01/2019. Clinical trial information: NCT03780517.

A first-in-human study of, NUC-7738, a 3'dA phosphoramidate, in patients with advanced solid tumors or lymphoma (NuTide 701).

TPS3147 Background: Nucleoside analogs form the backbone therapy for both hematological and solid malignancies. However, their clinical effectiveness is severely limited by key cellular resistance mechanisms linked to increased breakdown, impaired activation and transport. NUC-7738 is a phosphoramidate transformation of cordycepin (3’-deoxyadenosine; 3’-dA), a derivative of adenosine that was first isolated from Cordyceps sinensis. The cytotoxic effect of 3’-dA is largely attributed to intracellular generation of the triphosphate metabolite, 3’-dATP, terminating DNA and RNA synthesis. Although 3’-dA has shown potent anti-tumor activity in non-clinical studies, it has not been successful in clinical studies mainly because of rapid enzymatic degradation by adenosine deaminase. NUC-7738 is not a substrate for adenosine deaminase and has been designed to bypass the key resistance pathways which have limited the clinical effectiveness of cordycepin. Methods: NuTide:701 is a two-part, first-in-human Phase I study in patients with advanced solid tumors and lymphoma who have exhausted all standard treatment options. The primary objective is to determine the RP2D and schedule of NUC-7738. Secondary objectives include safety, PK/PD and anti-tumor activity. Part 1, in patients with advanced solid tumors, will establish the RP2D and dose administration schedule of NUC-7738 for Part 2. Part 2 will further evaluate the selected RP2D and designated dosing schedule in an expansion cohort of patients with advanced solid tumors or lymphoma. The study initiated in Q1 2019. Clinical trial information: NCT03829254.

Phase 1 trial of TLR9 agonist lefitolimod in combination with CTLA-4 checkpoint inhibitor ipilimumab in advanced tumors.

TPS2669 Background: Drugs targeting pathogen associated molecular patterns are an attractive strategy to stimulate the immune system. Toll-like receptors (TLR) have generated significant interest as an effective means of stimulating the immune system that result in the killing of tumor cells. TLR-9 agonists can function to promote an early immune response and are an appealing partner for combination with checkpoint blockade to improve immune activation. Lefitolimod (MGN1703) is a covalently closed dumbbell-shaped DNA molecule that functions as a TLR-9 agonist. We developed a clinical trial combining lefitolimod with ipilimumab (anti-CTLA4) in patients with advanced malignancies. In the dose-escalation phase 19 patients were enrolled and no DLTs were encountered. Safety data and maximum planned dose level of lefitolimod at 120mg weekly and ipilimumab 3mg/kg every 3 weeks was previously presented. Adverse events related to the combination included fatigue, appetite loss, rash, and anemia. Methods: This trial (NCT02668770) was designed to evaluate the safety profile and maximum tolerated dose of lefitolimod with ipilimumab. A 3+3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. Lefitolimod is administered via subcutaneous (SC) injection weekly while ipilimumab is given at 3mg/kg intravenous on day 8 of each 3 week cycle. Lefitolimod starting dose was 15mg SC weekly with 3 dose level escalations up to 120mg SC weekly. Patients receive treatment for 4 cycles (total 12 weeks) with the combination, and those with stable disease or response were eligible to remain on lefitolimod therapy for up to 1 year. Eligible patients have a metastatic or unresectable solid tumor refractory to standard therapies, ECOG ≤ 2, and normal organ and bone marrow function. Patients are allowed to have received prior checkpoint blockade agents. Enrollment in expansion cohorts in ongoing. To better understand relevant immunologic changes associated with treatment, paired pre- and post-treatment biopsies of target lesions and peripheral blood collection during treatment is required for target expansion cohort patient populations. In addition to evaluating target patient populations at the combination dose established during escalation, an expansion cohort for patients with cutaneous metastases involves combination treatment with intratumoral delivery of lefitolimod. Clinical trial information: NCT02668770.

Safety and clinical activity of the Notch inhibitor, crenigacestat (LY3039478), in an open-label phase I trial expansion cohort of advanced or metastatic adenoid cystic carcinoma

SummaryBackground Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911–17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line (n = 7) or ≥ third-line (n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC.

Altering the cytokine profile in the pancreatic cancer microenvironment with heat shock protein-90 inhibitors to enhance immunotherapy.

Abstract One feature of pancreatic ductal adenocarcinoma (PDAC) is the fibrotic stroma, which is a result of interactions between tumor cells, immune suppressive cells and pancreatic stellate cells (PSC). Stroma-derived cytokines including IL-6 represent a significant barrier restraining immunity against PDAC. Targeting pathways in the tumor microenvironment (TME) that regulate cytokine secretion can be an innovative means to improve access of effector immune cells to PDAC. We hypothesize that targeting Hsp90 can modulate the TME, through its ability to target inflammatory signaling and cytokine production by PSC and enhance the efficacy of immunotherapy. The Hsp90 inhibitor XL888 led to a concentration-dependent inhibition of IL-6 and MCP-1 production by PSC in vitro. Concurrently, PSC displayed growth inhibition as determined by MTT assay, and reduced alpha-SMA expression, a marker of cell activation. Inhibition of Jak/STAT and MAPK signaling was confirmed via immunoblot. These data compliment our published results indicating that Hsp90 inhibitors modulate survival pathways and PDAC growth in vitro and in vivo. This has led to an investigator-initiated Phase Ib/II clinical trial of XL888 (Hsp90i) and pembrolizumab (anti-PD-1) now accruing at our institution. Extensive laboratory correlative studies are ongoing to examine the impact of Hsp90 inhibition on anti-PD-1 mediated T cell proliferation, cytokine production, and impact on PSC-derived cytokine signatures. This work is being performed in paired biopsy samples (pre- and on-treatment), and peripheral blood from expansion cohorts of patients with metastatic pancreatic cancer (n=16) or colorectal cancer (n=16).

Abstract OT2-07-07: ATR inhibitor M6620 (formerly VX-970) with cisplatin in metastatic triple-negative breast cancer: Preliminary results from a phase 1 dose expansion cohort (NCT02157792)

Abstract Background: ATR is a critical regulator of the cellular response to replication stress; it signals DNA damage repair, mediated through homologous recombination. Many cancers depend on ATR to survive DNA damage. M6620 is a potent, selective inhibitor of ATR that augments the anticancer activity of cisplatin in preclinical triple-negative breast cancer (TNBC) models. Given the high prevalence of TP53 mutations in TNBC and limited platinum responsiveness in patients lacking a BRCA1/2 mutation, this study was designed to evaluate the safety and efficacy of M6620 in combination with cisplatin in an expansion cohort of patients with BRCA1/2 wild-type advanced/metastatic TNBC. Methods: Eligible patients had advanced/metastatic ER-, PR-, and HER2- breast cancer with 0-2 prior non–platinum-based therapies and measurable disease per RECIST 1.1. First line patients were eligible if relapse occurred ≥3 months after prior (neo)adjuvant chemotherapy. Of a maximum 50 patients planned for enrollment, ≥30 were required to have BRCA1/2 germline wild-type status and basaloid molecular subtype tumors on central testing. Patients received intravenous cisplatin 75 mg/m2 on day 1 with intravenous M6620 140 mg/m2 on days 2 and 9 of each 21-day cycle. In patients intolerant of cisplatin or at investigator's discretion, cisplatin could be switched to carboplatin AUC 5 with M6620 90 mg/m2. Results: At the time of abstract submission, 35 female patients were enrolled in this study; 18 patients with confirmed BRCA1/2 wild-type and basaloid metastatic TNBC who received ≥1 cycle of study drug and had ≥1 baseline scan and ≥1 on-treatment scan at the time of the data cut were included in the primary efficacy analysis. Median progression-free survival (PFS) was 4.1 months (90% CI, 1.6-6.9 months). PFS was ≥ 6 months in 2 patients and ≥ 3 months in 8 patients. Preliminary unconfirmed objective response [complete response or partial response (PR)] was observed in 38.9% (90% CI, 19.9%-60.8%) of patients. All 7 patients with preliminary objective response had PR as best overall response; the longest duration of response was 183 days. Response was ongoing in 4 patients with PR at the time of data cutoff. Grade ≥3 related treatment-emergent adverse events occurred in 16 of 35 patients: neutropenia (n=8), anemia (n=5), vomiting (n=4), nausea (n=3), and, in 1 patient each, thrombocytopenia, neutrophil count decreased, platelet count decreased, hypokalemia, generalized weakness, rigors, and acute kidney injury. Conclusions: Combination of M6620 and cisplatin shows encouraging antitumor activity and tolerability in patients with advanced/metastatic TNBC. The study is ongoing; updated safety and efficacy results will be presented. Citation Format: Telli ML, Lord S, Dean E, Abramson V, Arkenau H-T, Murias C, Becerra C, Tang R, Penney MS, Pollard J, Conboy G, Fields SZ, Shapiro G, Tolaney SM. ATR inhibitor M6620 (formerly VX-970) with cisplatin in metastatic triple-negative breast cancer: Preliminary results from a phase 1 dose expansion cohort (NCT02157792) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-07.

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer

Background:Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/δ activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo.Methods:A phase I, open-label, dose-escalation study to evaluate the safety, tolerability and recommended phase II dose (RP2D) of copanlisib with gemcitabine or with cisplatin plus gemcitabine (CisGem) in patients with advanced malignancies, including an expansion cohort in patients with biliary tract cancer (BTC) at the RP2D of copanlisib plus CisGem. Copanlisib and gemcitabine were administered on days 1, 8 and 15 of a 28-day cycle; maximum tolerated dose (MTD) and RP2D of copanlisib were determined. Copanlisib plus CisGem was administered on days 1 and 8 of a 21-day cycle; pharmacokinetics and biomarkers were assessed.Results:Fifty patients received treatment as follows: dose-escalation cohorts, n=16; copanlisib plus CisGem cohort, n=14; and BTC expansion cohort, n=20. Copanlisib 0.8 mg kg−1 plus gemcitabine was the MTD and RP2D for both combinations. Common treatment-emergent adverse events included nausea (86%), hyperglycaemia (80%) and decreased platelet count (80%). Copanlisib exposure displayed a dose-proportional increase. No differences were observed upon co-administration of CisGem. Response rates were as follows: copanlisib plus gemcitabine, 6.3% (one partial response in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12% (one complete response and three partial responses all in patients with BTC (response rate 17.4% in patients with BTC)). Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41% (12 out of 29).Conclusions:Copanlisib plus CisGem demonstrated a manageable safety profile, favourable pharmacokinetics, and potentially promising clinical response.

Abstract A083: A phase Ib study of the combination of MLN0128 (dual TORC1/2 inhibitor) and MLN8237 (Aurora A inhibitor, alisertib) in patients with advanced solid tumors

Abstract Background: MLN0128 is an oral inhibitor of mTOR kinase and mTORC1/2 signaling. Alisertib is an oral inhibitor of Aurora A kinase. Senescence and upregulation of genes in the PI3K/AKT/mTor pathway have been observed in triple-negative breast cancer (TNBC) patient-derived xenograft models treated with alisertib, with greater tumor growth inhibition demonstrated in combination with MLN0128 as compared to each agent alone. An investigator-initiated trial was developed to evaluate the combination of MLN0128 and alisertib in patients with advanced solid tumors, followed by an expansion cohort in metastatic TNBC and other selected cancers. The goals of this ongoing study are to evaluate safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of the combination. Results of dose escalation are presented here. Methods: Patients with advanced solid tumors refractory to standard therapy were treated orally at escalating doses with the combination of MLN0128 daily on a continuous schedule and alisertib twice daily (BID) on days 1-7 of a 21-day cycle. Dose escalation was conducted according to a standard 3+3 design. Key eligibility criteria included HgbA1c <7%, fasting serum glucose <130mg/dL and fasting triglycerides <300mg/dL, normal cardiac function, no condition with potential to cause excessive daytime sleepiness (including chronic hypoxia) and no risk of malabsorption of oral medications. PK assessments were performed at various time points after single-agent and combination dosing. Results: A total of 16 patients with refractory cancers were enrolled in dose escalation. No dose-limiting toxicity (DLT) was observed in dose level 1 (MLN0128 1mg/alisertib 30mg) or dose level 2 (2mg/30mg). At the third dose level (2mg/40mg) 2 of 7 patients experienced a DLT (grade 3 fatigue/confusion and grade 2 GERD/nausea leading to study discontinuation). In an alternate dose level cohort evaluating MLN0128 3mg and alisertib 30mg, 2 of 2 patients experienced a DLT of grade 3 fatigue. The maximum tolerated dose (MTD) of the combination was determined to be MLN0128 2mg daily and alisertib 30mg BID. Most common adverse events (AEs) of any grade included alopecia, diarrhea, fatigue and rash in 19% each and nausea in 31% of patients. Most common Grade 3 AEs included fatigue (19%) and decreased neutrophil count (31%). Dose modification was required in 56% of patients, most often due to neutropenia. Median time on study was 3 cycles (range 1-15) at data cutoff. Best response of stable disease was observed in 5 patients (31%), with prolonged stable disease noted in a patient with ER+/HER2- breast cancer (15 cycles) and a patient with castrate-resistant prostate cancer (10 cycles). PK assessments indicate no significant drug interaction between agents. Cmax was 24.7 (± 13.6) ng/mL for MLN0128 and 1049 (±363) ng/mL for alisertib at combination MTD doses. MLN0128 AUC was 128.2 (±72.7) ng/mLxhr and alisertib AUC0-8 was 6119 (±2331) ng/mlxhr at these doses. Conclusions: MLN0128 2mg daily on a continuous schedule and alisertib 30mg BID days 1-7 of a 21-day cycle is the MTD of the drug combination. An expansion cohort in patients with TNBC and other selected cancers is currently enrolling at this dose. Functional imaging and serial tumor biopsies are being integrated into this cohort to assess the pharmacodynamic interactions of the combination. Citation Format: S. Lindsey Davis, Elaine T. Lam, Bradley R. Corr, Cindy L. O'Bryant, Ashley Glode, Nichole Adler, Todd M. Pitts, John J. Tentler, Anna Capasso, Kyrie Dailey, Natalie J. Serkova, Colin D. Weekes, Daniel L. Gustafson, Christopher H. Lieu, Wells A. Messersmith, Stephen Leong, S. Gail Eckhardt, Jennifer R. Diamond. A phase Ib study of the combination of MLN0128 (dual TORC1/2 inhibitor) and MLN8237 (Aurora A inhibitor, alisertib) in patients with advanced solid tumors [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 A083.

ONC201: a new treatment option being tested clinically for recurrent glioblastoma.

Glioblastoma is an aggressive central nervous system tumor with a 5-year-survival rate of less than 10%. Patients diagnosed with the disease are treated with surgery, radiation and temozolomide chemotherapy. Despite survival benefits, patients eventually relapse. There is a need for new treatments with improved efficacy. Imipridone ONC201 is a small molecule originally identified as a TNF-related apoptosis inducing ligand (TRAIL)-inducing compound. ONC201 has the unique ability to induce expression of both pro-death ligand TRAIL and its receptor DR5 through engagement of the cellular integrated stress response (ISR) pathway. Arrillaga-Romany et al. report early results from futility analysis of a phase II clinical trial of ONC201 in 17 patients with recurrent or refractory glioblastoma conducted at the Massachusetts General Hospital Cancer Center. The results are promising, as ONC201 shows preliminary signs of efficacy. Further testing of ONC201 in an expansion cohort of patients with glioblastoma is ongoing.

An investigator-initiated phase I study of ONX-0801, a first-in-class alpha folate receptor targeted, small molecule thymidylate synthase inhibitor in solid tumors.

2503 Background: ONX-0801 is a first-in-class alpha folate receptor (AFR) targeted thymidylate synthase inhibitor, engineered to differentially accumulate 6000-fold in AFR overexpressing cancer cells. Methods: A 3+3 dose escalation design was used and two IV schedules were explored. Schedule A, weekly dosing (QW) and schedule B, once every 2 weeks dosing (Q2W). A cycle consisted of 4 weeks and treatment was stopped after 6 cycles in both schedules. An expansion cohort to evaluate clinical activity in patients with AFR overexpressing high grade serous ovarian cancer (HGSOC) was planned. Results: 21 patients each were treated in schedule A and B exploring doses ranging from 1-6 mg/m2 and 2-12 mg/m2, respectively. The dose limiting toxicity on schedule A was G3 cellulitis; no dose limiting toxicity was seen on schedule B. The most common toxicities were fatigue 15/42 (36%), nausea 9/42 (21%) and dysgeusia 5/42 (12%). Within schedule A at 4 mg/m2, 2 patients developed suspected drug-related changes on pulmonary function tests (drop in Dlco > 15%) at cycles 5 and 6, respectively. No cases of suspected drug-related drop in Dlco were noted in patients treated in schedule B. No grade 3-4 diarrhea, mucositis or neutropenia were seen in either cohort. The Cmax, AUC and half-life at 12 mg/m2 were 4952 ng/mL, 85170 h*ng/mL and 26 h, respectively. Pre-clinical PK-PD modelling aimed to achieve concentrations between 0.05-1 µM and this was achieved for periods of 48 h at doses of 4 mg/m2and above. Based on safety and PK, the recommended phase II dose (RP2D) of ONX-0801 was 12 mg/m2 Q2W and an expansion in patients with HGSOC is ongoing. 5 patients with HGSOC had partial responses (PRs) in the dose escalation cohort. In the current expansion cohort in patients with HGSOC, 5/11 patients had PRs. Archival samples have been analyzed from 8/11 patients in the expansion cohort. 4/4 AFR+ve and 4/4 AFR-ve patients did and did not have a PR following treatment with ONX-0801, respectively. Conclusions: The RP2D of ONX-0801 is 12 mg/m2 Q2W. At the RP2D, multiple patients with AFR overexpressing HGSOC have had PRs and further randomized biomarker prespecified phase II trials are warranted. Clinical trial information: NCT02360345.

Phase 1 multicenter trial of CUDC-907 in children and young adults with relapsed or refractory solid tumors, CNS tumors, and lymphoma.

TPS10576 Background: CUDC-907 is an oral first-in-class small molecule inhibitor of histone deacetylases (HDACs) and phosphatidylinositol-3-kinases (PI3Ks), two enzyme classes commonly implicated in pediatric malignancies. Preclinical data demonstrate that inhibition of these enzymes decreases tumor growth across a range of histologies. Data from preclinical and clinical studies suggest that down-regulation of Myc or Mycn signaling may be important in the antineoplastic effects of CUDC-907. Myc or Mycn signaling appears to drive a number of pediatric cancers, heralds a poor prognosis in many of these diseases and has proven difficult to target. CUDC-907 has completed adult phase I testing in patients with hematologic malignancies. The drug was tolerable using a 5 days on/2 days off (5/2) dosing strategy, with a recommended phase II dose of 60 mg. Diarrhea, fatigue, nausea and thrombocytopenia were the most commonly reported side effects. Partial and complete responses were observed in patients with Myc-altered diffuse large B cell lymphoma. Methods: This study is a phase I, open-label, multicenter trial of CUDC-907 in patients 1-21 years of age with relapsed/refractory solid tumors, brain tumors and lymphomas (NCT02909777). The primary objectives are to determine the recommended phase II dose, describe toxicities, and describe pharmacokinetic parameters of CUDC-907 in this population. Other objectives include evaluation of disease response and exploration of the pharmacodynamic effects of CUDC-907. Patients receive CUDC-907 orally on a 5/2 schedule in 28-day cycles, with a pediatric mini-tab formulation available for younger children. Part A consists of a standard 3+3 design evaluating up to three dose levels. Following dose escalation, Part B consists of two expansion cohorts for patients with Mycn/Myc-driven neuroblastoma or mature B-cell lymphoma. Up to 44 patients may be enrolled across Parts A and B. Detailed pharmacokinetic testing is required in the first two cycles. Optional pharmacodynamic testing will quantify histone acetylation, Myc protein, and phospho-S6 in serial blood samples. Enrollment began in October 2016 and is ongoing. Clinical trial information: NCT02909777.

A phase 1, multicenter, dose-escalation study of PRN1371, an irreversible covalent FGFR1-4 kinase inhibitor, in patients with advanced solid tumors, followed by expansion cohorts in patients with FGFR genetic alterations.

TPS2616 Background: FGFR inhibition is a promising and clinically proven therapeutic approach in a number of solid tumors where genetic alterations of FGFR drive oncogenesis. PRN1371 is a highly selective oral, irreversible inhibitor of FGFR1-4 that exhibits high potency in cancer cell lines harboring FGFR alterations, including mutations and fusions. Methods: Part A of this phase 1 clinical trial explores ascending doses of PRN1371 in adult patients with advanced solid tumors in a "3 + 3" design, where cohorts of three patients are studied at each level until additional patients need to be added to better assess safety, establish the maximum tolerated dose and define the recommended phase 2 dose (RP2D). PRN1371 is dosed once or twice daily in continuous, 28-day cycles until disease progression. Part B studies include two or three expansion cohorts of different tumor types, 10 patients each with FGFR1-4 gene mutations, fusions, or amplification at the RP2D. The on-target effect of serum phosphorus and FGF23 increases are measured as potential pharmacodynamic biomarkers. Elevated serum phosphorus is managed with oral phosphate binding medications and a low phosphate diet, with dose interruptions and use of acetazolamide if certain thresholds are exceeded. Circulating tumor DNA from patients at baseline and during follow up is analyzed for FGFR genetic alterations. Pre and on-treatment tumor biopsies in Part B will be tested for a panel of pharmacodynamic biomarkers of FGFR inhibition. Clinical trial information: NCT02608125.