Durable Partial Response Research Articles

Checkmate 205 Update with Minimum 12-Month Follow up: A Phase 2 Study of Nivolumab in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma

Checkmate 205 Update with Minimum 12-Month Follow up: A Phase 2 Study of Nivolumab in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma

Safety and activity of IT-139, a ruthenium-based compound, in patients with advanced solid tumours: a first-in-human, open-label, dose-escalation phase I study with expansion cohort

ObjectiveThis phase I clinical study (NCT01415297) evaluated the safety, tolerability, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of IT-139 (formerly NKP-1339) monotherapy in patients with advanced solid tumours. IT-139, sodium trans-(tetrachlorobis(1H-indazole)ruthenate(III)), is a novel small molecule that suppresses the stress induction of GRP78 in tumour cells. GRP78 is a key regulator of misfolded protein processing, and its upregulation in tumours is associated with intrinsic and drug-induced resistance.MethodsForty-six patients with advanced solid tumours refractory to treatment received intravenous infusions of IT-139 on days 1, 8 and 15 for every 28 days, and doses were evaluated across nine cohorts at 20, 40, 80, 160, 320, 420, 500, 625 and 780 mg/m2.ResultsOverall, IT-139 was well tolerated. The treatment-emergent adverse events (AEs) occurring in ≥20% of patients were nausea, fatigue, vomiting, anaemia and dehydration. The majority of patients had AEs that were ≤grade 2, regardless of relationship with the study drug. Of the total 38 efficacy-evaluable patients, one patient with a carcinoid tumour achieved a durable partial response. Nine additional patients achieved stable disease . The MTD was determined to be 625 mg/m2. IT-139 exhibited first-order linear pharmacokinetics.ConclusionsIT-139 demonstrated a manageable safety profile at the MTD and modest anti-tumour activity in this study of patients with solid tumours refractory to treatment. The lack of dose-limiting haematological toxicity and the absence of neurotoxicity position IT-139 well for use in combination with a broad spectrum of anticancer drugs.Trial registration numberNCT01415297.

Chromoplectic TPM3–ALK rearrangement in a patient with inflammatory myofibroblastic tumor who responded to ceritinib after progression on crizotinib

Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas that can occur at any age. Surgical resection is the primary treatment for patients with localized disease; however, these tumors frequently recur. Less commonly, patients with IMTs develop or present with metastatic disease. There is no standard of care for these patients and traditional cytotoxic therapy is largely ineffective. Most IMTs are associated with oncogenic ALK, ROS1 or PDGFRβ fusions and may benefit from targeted therapy. We sought to understand the genomic abnormalities of a patient who presented for management of metastatic IMT after progression of disease on crizotinib and a significant and durable partial response to the more potent ALK inhibitor ceritinib. The residual IMT was resected based on the recommendations of a multidisciplinary tumor sarcoma tumor board and analyzed by whole-genome mate pair sequencing. Analysis of the residual, resected tumor identified a chromoplectic TPM3-ALK rearrangement that involved many other known oncogenes and was confirmed by rtPCR. In our analysis of the treatment-resistant, residual IMT, we identified a complex pattern of genetic rearrangements consistent with chromoplexy. Although it is difficult to know for certain if these chromoplectic rearrangements preceded treatment, their presence suggests that chromoplexy has a role in the oncogenesis of IMTs. Furthermore, this patient's remarkable response suggests that ceritinib should be considered as an option after progression on crizotinib for patients with metastatic or unresectable IMT and ALK mutations.

Abstract 2996: IT-139 targets GRP78 in stressed cancer cells

Abstract IT-139, sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] is a first in class small molecule that has successfully completed a phase I clinical trial against solid refractory cancers. 11 of 41 patients achieved stable disease with manageable side effects and 8 patients showed tumor size reduction including a durable partial response. Preclinical studies suggest IT-139 down-regulates the chaperone GRP78, but the mechanism of action is not fully understood. GRP78 (also known as BiP and HSPA5) is the primary sensor and regulator of the endoplasmic reticulum (ER). In cancer cells it is preferably expressed on the cell surface, but also translocates to the mitochondria and cytosol where it regulates critical oncogenic signaling pathways, thus making GRP78 an excellent target for therapy. Here we show in vitro results of IT-139 treatment in a panel of cancer cell lines. IC50 levels measured at 72 hour varied ranging from 15 μM to 180 μM. Annexin V/PI staining by flow cytometry in HCT-116, HT-29, A375 and A549 cell lines at 24 hour show early and late apoptosis, which corresponds to their relative IC50s. UPR induction and overexpression of GRP78 has been reported to cause cell cycle arrest in G1. But in IT-139 treated cell lines HCT116, HT-29, A549 and LnCAP, cell cycle arrest occurred in G2, whereas in A375 cells IT-139 induced cell cycle arrest at G1. These data suggest an inhibition of GRP78 levels and that cell cycle arrest status is also dependent upon the cell line. Electron microscopic (EM) images of HCT-116 and HT-29 cells treated with IT-139 at 24 hours showed significant vacuolization, ER expansion and disorganization of intracellular organelles, strongly suggesting ER stress. However, there is an absence of double membrane vacuoles or autophagosome formation in response to the ER stress. Also, immunofluorescent analysis displayed no LC3-II punctate distribution, although protein immunoblots showed LC3 and p62 protein levels increasing in IT-139 treated cells. These data suggest an inhibition of autophagy. Additionally, EM images showed vacuolated mitochondria and distortion of cristae. In all cell lines treated with IT-139 even below their corresponding IC50 concentration, JC-1 staining showed an increased loss of mitochondrial membrane potential. These observations hypothetically indicate an inhibition of stress-induced GRP78. Quantitative real-time PCR showed IT-139 treatment in combination with thapsigargin exhibits a significant fold change decrease in the GRP78 mRNA expression. These results suggest that IT-139 downregulates GRP78 leading to an increase in ER stress, mitochondrial damage, decreased autophagy, increased apoptosis and cell death. Citation Format: Jyothi Sethuraman, Tara Lee Costich, Tomas Vojkovsky, Rick Crouse, Valentin Cognet, Suzanne Bakewell. IT-139 targets GRP78 in stressed cancer cells. [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 2996.

Imatinib and dasatinib as salvage therapy for sclerotic chronic graft-vs-host disease.

AimTo assess the toxicity, tolerance, steroid-sparing capacity, effectiveness, and response rate to imatinib and dasatinib for the treatment of severe sclerotic chronic graft-vs-host disease (scGVHD).MethodsThis retrospective study analyzed 8 consecutive patients with severe refractory scGVHD who received salvage therapy with imatinib. Patients intolerant and/or refractory to imatinib received dasatinib treatment.Results7 patients discontinued imatinib treatment (1 achieved complete response, 5 were resistant and/or intolerant, and 1 developed grade IV neutropenia) and 1 patient achieved prolonged partial response, but died due to an infectious complication while on treatment. 5 patients started dasatinib treatment (3 achieved partial responses and discontinued dasatinib, 1 achieved a durable partial response, but died due to a consecutive rapid pulmonary cGVHD progression and 1 with stable disease discontinued treatment due to gastroenteric intolerance). The response rate (partial and/or complete responses) for severe scGVHD was 25% for imatinib and 60% for dasatinib.ConclusionIn our series, dasatinib was better tolerated, safer, steroid-sparing, and had a low incidence of infectious complications, which suggests that it may be a more effective therapeutic alternative for patients with refractory scGVHD than imatinib. Treatment of scGVHD with effective antifibrotic drugs such as TKI, which block the kinase fibrotic pathway, may be a safe and effective therapeutic option, but further studies are needed to confirm our findings.

Total 18F-FDG PET/CT Metabolic Tumor Volume Is Associated With Postoperative Biochemical Response in Patients With Metastatic Pheochromocytomas and Paragangliomas.

The aim of this pilot study was to determine if metabolic tumor volume (MTV) and total lesion glycolysis (TLG) could serve as predictors of biochemical remission and pharmacotherapy-free interval in patients with metastatic pheochromocytomas (PCCs) and paragangliomas (PGLs). Patients with metastatic PCCs/PGLs have a high rate of biochemical recurrence, which can be associated with increased cardiovascular morbidity. Predictors of biochemical response are needed to guide and select patients who may benefit from therapy. Whole body MTV and TLG was calculated from preoperative 18F-FDG PET/CT scans and analyzed as marker of biochemical response and pharmacotherapy-free interval. Seventeen patients underwent a total of 19 procedures, with a median follow-up time of 26.4 months. Whole body MTV of patients with biochemical recurrence (n = 13, mean 73.8 mL) was higher than those who had a biochemical response (n = 6, mean 14.7 mL, P = 0.05). Patients with low MTV (<37.2 mL) had an improved durable partial biochemical response (P < 0.05), and a statistical trend for complete biochemical remission (P = 0.07) and pharmacotherapy-free interval (P = 0.06). In 8 patients with metastatic disease outside the abdomen, 4 patients had less than 35% of their disease burden outside the abdomen and these patients had a more durable partial biochemical response compared to patients with greater than 35% of their disease burden outside the abdomen (P < 0.05). Whole body MTV and TLG represents novel and valuable predictors of biochemical response for patients with metastatic PCCs and PGLs. A larger prospective study should be performed to validate these findings.

Prolonged response to pemetrexed-based chemotherapy in a patient with peritoneal mesothelioma: a case report and review of the literature

Abstract Peritoneal mesothelioma is a rare tumor typically presenting with ascites and associated with occupational asbestos exposure with a latency period of 20–40 years. Intensive multi-modality approach combining cytoreductive surgery, intraperitoneal chemotherapy and possibly radiotherapy can be considered, but otherwise the prognosis is rather poor. Palliative chemotherapy may be an option in these rare cases. However, no approved systemic treatment exists for peritoneal mesothelioma. We present here a patient with peritoneal mesothelioma who was treated with the combination of pemetrexed with cisplatin shortly after the failure of hyperthermic intraperitoneal chemotherapy. The patient experienced durable partial response to the treatment, resolution of ascites, and returned to his normal daily life activities. With the exception of palliative chemotherapy in case of patients in good condition, therapeutic options in patients with peritoneal mesothelioma are currently very limited. The combination of pemetrexed and cisplatin can lead to long-term control in selected patients.

Abstract P6-13-15: Lyso-thermosensitive liposomal doxorubicin shows efficacy with minimal adverse events in patients with breast cancer recurrence at the chest wall

Abstract INTRODUCTION: Local-regional recurrence after definitive treatment of breast cancer is reported in 5 – 40 % of patients depending risk factors and initial treatment. Chest wall recurrence is associated with poor quality of life and limited treatment options. Lyso-thermosensitive liposomal doxorubicin (LTLD, Thermodox®) is an intravenously administered agent designed to selectively release doxorubicin when exposed to temperatures ≥39.5° C at a targeted tumor. Hyperthermia, the elevation of tissue temperature in the range of 40° C to 44° C, causes direct cytotoxicity, enhanced blood flow, and oxygenation. We are reporting the interim findings of an ongoing Phase I/II Study Evaluating the Maximum Tolerated Dose, Bioequivalence/Pharmacokinetics, Safety, and Efficacy of LTLD in Patients with Local-Regional Recurrent Breast Cancer. Final results will be presented in December. METHODS: Patients with breast carcinoma on the chest wall with progression following radiation were eligible; prior chemotherapy and hormone therapy were allowed. LTLD was administered intravenously followed immediately by hyperthermia in up to two treatment fields for 1 hour per field for a goal of 40–42°C. Response was measured using clinical assessment, CT, and digital photos. All subjects were assessed for safety. Up to six cycles of LTLD/hyperthermia were administered depending on disease progression or tolerance. A total of 11 patients were enrolled on the Phase I portion of the study and 9 were evaluable for efficacy review. To date, 17 patients are enrolled on the Phase II portion of the study and 13 are evaluable for efficacy review. Once 12 patients are found to be evaluable for PK the primary endpoint of bioequivalence can be evaluated. RESULTS: A dose of 50 mg/m2 was recommended by the DSMB at completion of the Phase I study. Seven subjects were dosed at 50mg/m2, two patients developed a localized reaction in the treatment area consisting of erythema, woody induration, and pain which resolved with discontinuation of treatment. Twenty patients were dosed at 40mg/m2 without recurrence of symptoms. To date, twenty-eight patients were enrolled in the phase I/II study; one subject was excluded due to dose modification following 2 cycles of ThermoDox at a dose of 50mg/m2 to 40mg/m2 at cycle 3. This subject had a durable partial response. The tables summarize the safety and efficacy data. All efficacy data is investigator reported. Combined Phase I/II Safety DataSafety Data40 mg/m2 (N=20)50 mg/m2 (N=7)Any AE Event (n, %)17 85.07 100.0Grade 3+ AE (n, %)10 50.06 85.7Serious AE (n, %)5 25.03 42.9Hematological AE (n, %)10 50.07 100.0Deaths due to AE (n, %)0 0.00 0.0 Combined Phase I/II Efficacy DataEfficacy Data40 mg/m2 (N=20)50 mg/m2 (N=7)Responders (Partial &amp; Complete) (n, %)10 50.03 42.9Complete Response (n, %)5 25.01 14.3Partial Response (n, %)5 25.02 28.6Durable Response (lasting ≥ 3 months) (n, %)3 15.00 0.0 CONCLUSION: These findings suggest that LTLD at a dose of 40 mg/m2 combined with hyperthermia offers a promising and well tolerated treatment option for patients with recurrent chest wall disease from breast cancer. Additional data will be presented based on full trial accrual. Citation Format: Rugo H, Pabbathi H, Shrestha S, Aithal S, Borys N, Musso L, Zoberi I. Lyso-thermosensitive liposomal doxorubicin shows efficacy with minimal adverse events in patients with breast cancer recurrence at the chest wall. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-15.

Advances in immunotherapy for melanoma.

In recent years, the introduction and Federal Drug Administration approval of immune checkpoint inhibitor antibodies has dramatically improved the clinical outcomes for patients with advanced melanoma. These antagonist monoclonal antibodies are capable of unleashing dormant or exhausted antitumor immunity, which has led to durable complete and partial responses in a large number of patients. Ipilimumab targets the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor. Nivolumab and pembrolizumab target programmed cell death protein 1 (PD-1) receptors and have proven to be superior to ipilimumab alone. The combination of ipilimumab and nivolumab has yielded higher response rates, greater tumor shrinkage, and longer progression-free survival than either monotherapy alone. As other promising immunotherapies for melanoma proceed through clinical trials, future goals include defining the role of immune checkpoint inhibitors as adjuvant therapy, identifying optimal combination strategies, and developing reliable predictive biomarkers to guide treatment selection for individual patients.

The efficacy and safety of vinflunine in second-line therapy of patients with disseminated transitional cell carcinoma of the urinary tract in clinical practice

Objective: to investigate the safety of vinflunine, the rate and duration of its treatment response, progression-free and overall survival rates in patients receiving this drug in routine clinical practice for first-line chemotherapy (CT) – resistant disseminated transitional cell carcinoma of the urinary tract. Materials and methods. This retrospective observational multicenter study included data on 25 patients with verified disseminated transitional cell carcinoma of the urinary tract who took vinflunine for tumor progression after first-line CT performed in 11 Russian clinical centers in 23 March 2013 to 26 June 2016. The median age of the patients was 60 (44‒81) years. Their baseline somatic status was rated as ECOG 0 in 1 (4.0 %) patient, ECOG 1 in 13 (52.0 %) patients, EGOG 2 in 9 (36.0 %), and ECOG 3 in 2 (8.0 %). The most common sites of tumor foci were bones (n = 14, 56.0 %), lymph nodes of different groups (n = 14; 56.0 %), and lung (n = 9; 36.0 %). Results. Adverse reactions were recorded in 24 (96.0 %) cases. The most common types of toxicity were asthenia (n = 19; 76.0 %), anemia (n = 18; 72.0 %), neutropenia (n = 13; 52 %), and nausea (n = 12; 48.0 %). Most adverse events were grades I–II and well controlled. There were no deaths due to adverse events. The best treatment response was regarded as partial in 6 (24.0 %) patients; stabilization and progression were observed in 10 (40.0 %) and 9 (36.0 %) patients, respectively. The median duration of partial response was 5.1 (95 % confidence interval (CI), 0.6–15.0) months; that of stabilization was 3.4 (95 % CI, 1.2–6.3) months. In all the 25 cases, the median progression-free and overall survival rates were 3.7 (95 % CI, 2.1‒5.3) and 6.5 (95 % CI, 5.2‒7.8) months, respectively. The somatic status was a predictor of overall survival (p < 0.0001). Conclusion. The efficacy and safety of vinflunine in second-line therapy for first-line CT-resistant disseminated transitional cell carcinoma of the urinary tract in unselected patients agree with those previously observed in Phase III randomized trial.

Clinical Trial Results from the Subgroup of Lymphoma/CLL in a Phase 1 Study of ARQ 092, a Novel Pan AKT-Inhibitor

Background: ARQ 092 is an oral allosteric, potent and selective AKT inhibitor with in vitro and in vivo activity in solid and hematological tumors. ARQ 092-101, the first clinical trial of ARQ 092, has enrolled more than 100 subjects with advanced solid tumors or recurrent malignant lymphoma. As reported previously, the dose escalation portion of the study has been completed and two dosing schedules (intermittent and weekly), are recommended for phase 2 studies. The recommended phase 2 dose (RP2D) for the intermittent dosing schedule is 200 mg once daily (QD) (one week on, one week off) and for the weekly dosing schedule is 300 mg twice daily (BID) (one day on, six days off). [1, 2] Enrollment in an expansion cohort at RP2Ds is ongoing. Here we report the results from 11 subjects with lymphoma/CLL.Material and Methods: Subjects with lymphoma/CLL have been enrolled and treated in the dose escalation and expansion cohorts with intermittent or weekly dosing schedule at the RP2Ds. Tumor responses for subjects with lymphoma were evaluated based on the Revised Response Criteria for Malignant Lymphoma. Adverse events were evaluated based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Blood samples were collected for PK analysis. Archival or biopsy tumor tissue samples were collected for genetic analysis.Results: As of 15 Jun 2015, 11 subjects with lymphoma/CLL (73% male; median age 78 years; 5 follicular, 3 mantle cell, 2 diffuse large B cell, 1 CLL; 4 in dose escalation cohorts, 7 in expansion cohort) have been enrolled and treated at initial doses of 120 to 270 mg QD intermittently (n=7) or 300 mg BID weekly (n=4). All subjects have received at least one prior systemic therapy (median 2, range 1-6).Median duration on study treatment for all 11 subjects was 8 weeks (range 1 to 30 weeks).One subject with CLL and two with follicular lymphoma experienced durable partial responses, respectively with times to response of 8, 8 and 24 weeks and response durations of 16, 8+, and 2+ weeks. The two follicular PR subjects, one of whom had an AKT1 (E17K) mutation, remain on study treatment. In addition, one subject with follicular and one with mantle cell lymphoma experienced stable diseases. Four subjects experienced progressive diseases and two were not evaluable for tumor responses due to early consent withdrawal and clinical disease progression.Table 1Common drug-related adverse events (≥10%) included macula-papular rash 45%, hyperglycemia 36%, mucosal inflammation 18% and stomatitis 18%.ResponseFollicular N=5CLL N=1Mantle cell N=3Diffuse large B cell N=2Total N=11PR213SD112PD1214NE112ORR40%100%0%0%27%DCR60%100%33%0%45%Conclusions: The safety profile of lymphoma subjects is consistent with subjects with solid tumors enrolled in this study. Preliminary signs of single agent activity have been documented with 3 PRs in heavily pretreated lymphoma/CLL including one with AKT1 (E17K) mutation.[1] First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts. M. Saleh et al., Abstract LB-197, AACR 104th Annual Meeting, 6-10 Apr 2013. Washington, D.C. U.S.[2] First-in-human study with ARQ 092, a novel pan AKT-inhibitor, in subjects with advanced solid tumors or recurrent malignant lymphoma. M. Saleh et al., Abstract 320, EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics , 18-21 Nov 2014, Barcelona, Spain DisclosuresHarb:Onyx Pharmaceuticals: Consultancy. Chai:ArQule, Inc.: Employment. Larmar:ArQule, Inc.: Employment. Abbadessa:ArQule, Inc.: Employment. Schwartz:ArQule, Inc.: Employment.

Abstract A79: Comprehensive genomic profiling (CGP) of adult granulosa cell tumors (aGCT) identifies clinically relevant genomic alterations (CRGA) and targeted therapy options

Abstract Background: Adult granulosa cell tumors account for ∼70% of sex cord stromal tumors of the ovary. Most behave as low-grade malignancies and present as stage I disease. However 20% recur, often after a prolonged time (median time to recurrence 6 years). Current therapeutic options (bleomycin/etoposide/cisplatin (BEP), hormone therapy, bevacizumab) have shown modest efficacy in the setting of advanced or recurrent disease. Prior genomic studies of aGCT identified recurrent FOXL2 mutations as characteristic of this tumor type, however this mutation is not currently amenable to targeted therapy. We present the CGP of 70 advanced/recurrent stage aGCT with identification of CRGAs and include a description of a patient response to CGP-matched targeted therapy. Methods: DNA was extracted from 70 FFPE aGCT clinical specimens. Hybridization captured libraries of 236 (FoundationOne, n = 28) or 315 (FoundationOne, n = 42) genes, plus select introns frequently rearranged in cancer, which were sequenced to high (median 780x), uniform coverage. All classes of genomic alterations (base subs, small in/dels, rearrangements, and copy number alterations) were evaluated and reported. CRGA were defined as GA associated with on-label targeted therapies and targeted therapies in mechanism-driven clinical trials. Results: 70 samples, 10% from primary site tissue and 90% from metastatic sites were included. The patients were women aged 30-80 (median 56.5y) with predominantly advanced stage aGCT. 68 cases (97%) had the FOXL2 402C&amp;gt;G mutation and 61% of cases had at least one additional GA (total n = 165) including 37 different genes (avg 2.4 GA per tumor) of which 27 were CRGA (avg 0.44 per tumor). 40% of aGCT cases featured ≥ 1 CRGA, including 14 (20%) cases with CRGA in the PI3K/Akt/mTOR pathway. The most common CRGAs observed were: MLL2 (10%),PIK3CA (8.6%), CDKN2A/B (8.6%), AKT1 (4.3%), KRAS (4.3%); and NRAS (2.8%). To date, we are aware of one patient with an AKT1 missense mutation in the pleckstrin homology domain (AKT1 Q79K) who showed a durable 6-month partial response to AKT-directed targeted treatment. Conclusions: Almost two-thirds of advanced stage aGCT demonstrate GAs in addition to the pathognomonic FOXL2 mutation. 40% of cases demonstrate other targetable mutations, most commonly in the PI3K/Akt/mTOR pathway which present the opportunity for targeted therapy. This first account of a clinical response to CGP-directed targeted therapy in aGCT demonstrates potential efficacy of an AKT inhibitor in a subset of patients suffering from this otherwise treatment refractory tumor. Patients who have exhausted other SOC therapy for metastatic aGCT may similarly achieve clinical benefit from CGP-directed therapeutic decision- making and this provides support for development of further mutation-matched therapeutic trial designs. Citation Format: Michelle Rowland, Scott McMeekin, Kathleen Moore, Mark Bailey, Siraj M. Ali, Rosemary Zuna, Jo-Anne Vergilio, James Suh, Juliann Chmielecki, Garrett M. Frampton, Doron Lipson, Philip J. Stephens, Vincent A. Miller, Jeffrey S. Ross, Julia A. Elvin. Comprehensive genomic profiling (CGP) of adult granulosa cell tumors (aGCT) identifies clinically relevant genomic alterations (CRGA) and targeted therapy options. [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 A79.

Abstract B183: Targeting PI3K pathway dependent endometrial tumors with allosteric AKT inhibitors, ARQ 092 and ARQ 751

Abstract Background: In endometrial cancer more frequently than in other tumors, abnormal activation of the AKT pathway drives tumorigenesis and can be induced by both PI3K and AKT alterations, being associated with aggressive disease and poor prognosis. ARQ 092 is a highly selective, allosteric, potent AKT inhibitor currently under clinical investigation, and ARQ 751 is the next generation AKT inhibitor, with different physical-chemical properties. Methods: ARQ 092 and ARQ 751 were profiled using a Cell-TiterGlo® viability assay and the inhibition of AKT and downstream targets were measured by Western and immunohistochemistry analyses in an AN3CA endometrial cell line with activated PI3K (via PIK3R1 mutation). The efficacy and pharmacodynamics effect of ARQ 092 and ARQ 751 on phospho-AKT and phospho-pRAS40 were determined in AN3CA xenografts after repeated daily oral dosing. ARQ 092 was also tested against 23 endometrial patient-derived tumor models (PDX). Lastly, endometrial cancer patients are being enrolled in the expanded cohort of ARQ 092-101, a phase 1 study, at 2 schedules: intermittent (200mg once a day, 1 week on, 1 week off) or weekly (300mg twice daily, 1 day on, 6 days off). Results: In AN3CA cell lines, ARQ 092, and more potently ARQ 751, inhibited AKT signaling including inhibition of phosphorylation of downstream targets in a dose dependent manner. Both inhibitors exhibited strong anti-proliferative activity. However, while ARQ 092 inhibited 6 out of 9 cell lines with GI50 below 1 μM, ARQ 751 inhibited all 5 cell lines with GI50 below the 150 nM range. Of the 22 tested PDX models, 12 responded (&amp;gt;50% tumor control compared to placebo). Both ARQ 092 and ARQ 751 exhibited over 90% AKT inhibition after 6 hrs exposure to a 40 mg/kg dose in an AN3CA mouse xenograft. In this model, at the maximum tolerated dose of 120mg/Kg, ARQ 092 and ARQ 751 resulted in 79% and 92% tumor growth reduction, respectively. Additionally, for ARQ 092, plasma Cmax in mouse models at the 100 mg/kg dose was compared to the Phase I human results. Plasma Cmax in mice was 2.1 μM whereas in patients enrolled at the intermittent and weekly schedules Cmax were 1.3 and 1.5 μM, respectively. Of the 19 enrolled patients with endometrial cancer, only one was treated at full dose, had a PIK3CA mutation (H1047R), and obtained a durable partial response after 2 months on therapy. Conclusions: Both ARQ 092 and ARQ 751 demonstrated potent inhibition of p-AKT and downstream pathway signaling. In addition, both compounds exhibited potent antitumor activity in human endometrial cancer cells in vitro and in vivo. Such preclinical observations were recapitulated in the clinic by the rapid objective response observed in the first endometrial patient with PIK3CA mutation enrolled at full dose in the expanded cohort of the ongoing ARQ 092-101 Phase I clinical trial. Overall, these data provide a strong mechanistic rationale for further evaluation of ARQ 092, and possibly ARQ 751, in patients with PI3K-driven endometrial malignancies. Citation Format: Sudharshan Eathiraj, Brian Schwartz, Yi Yu, Michael J. Wick, Terence Hall, Feng Chai, Jasgit Sachdev, Giovanni Abbadessa. Targeting PI3K pathway dependent endometrial tumors with allosteric AKT inhibitors, ARQ 092 and ARQ 751. [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 B183.

Abstract IA19: Curative potential of T-cell immunotherapy for cancer

Abstract Adoptive cell transfer (ACT) immunotherapy for patients with metastatic melanoma using autologous tumor infiltrating lymphocytes (TIL) mediated a 56% objective response rate including 20% of patients with durable complete regression ongoing from 6.7 to 10.3 years. Administration of autologous TIL to 9 patients with HPV induced metastatic cervical cancer mediated objective responses in 3 patients including 2 complete regressions that are ongoing beyond a year. The ideal targets for ACT are the unique mutations that occur in cancers. Using deep exomic sequencing a technique has been developed to identify any cancer mutation, presented on any of the patient's MHC molecules, that gives rise to reactive T cells. We recently reported the successful application of this approach to treat a patient with a metastatic bile duct cancer. Since virtually all cancers contain mutations this approach is now being vigorously studied to expand the current reach of cancer immunotherapy to common epithelial cancers. Genes encoding conventional alpha-beta T cell receptors (TCR) or chimeric antigen receptors (CAR) can be efficiently transduced into autologous lymphocytes though choosing suitable targets expressed on the cancer is critical to avoid toxicities to essential normal tissues. ACT using CARs to target the CD19 molecule present on normal B cells as well as on the great majority of B cell lymphomas and leukemias was first reported to successfully treat a patient with refractory lymphoma in 2010 in a patient who remains progression-free at five years. Durable complete and partial responses have been seen in patients with chemotherapy refractory indolent and aggressive large B cell lymphomas. Of 9 heavily pretreated patients with large cell lymphomas receiving ACT, 4 patients have had complete regressions, 3 ongoing from 9 to 22 months and 2 additional patients have had partial responses. Cancer-testes antigens such as NY-ESO-1 and MAGE-A3 are expressed during fetal development and in 10 to 80% of cancers from multiple tissues but are often not expressed in adult normal tissues. ACT targeting NY-ESO-1 resulted in a 67% response rate in 15 treated patients with refractory synovial cell sarcoma and a 53% response rate in 19 patients with melanoma including durable complete regressions. Shared mutations that are unique to an individual cancer type also represent excellent targets for cell transfer immunotherapy and we are conducting a trial using a CAR targeting the EGFRvIII mutation expressed in about 40% of patients with high grade glioblastoma Citation Format: Steven A. Rosenberg. Curative potential of T-cell immunotherapy for cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA19.

ImmTACs: bi-specific TCR-based reagents for targeted cancer immunotherapy (VAC7P.1037)

Abstract ImmTACs (immune mobilizing monoclonal T cell receptors against cancer) are a new class of soluble bi-specific reagent that exploit the natural antigen recognition pathway mediated by the T cell receptor (TCR). As TCRs recognise HLA-presented peptides, ImmTACs can access the larger pool of intracellular tumor antigens unavailable to antibody based therapies. ImmTACs target tumors via a soluble monocloncal TCR, engineered to recognise a given tumor associated peptide-HLA complex with exceptionally high sensitivity and specificity. Once bound to their target, ImmTACs redirect host polyclonal T cells via an anti-CD3 antibody fragment. In this way ImmTACs facilitate targeted T cell recognition of tumors leading to potent T cell activation and tumor cell killing, with the potential to break T cell tolerance. ImmTACs are specific for humans, thus efficacy, specificity and off target effects cannot be assessed in animal models. Using antigen positive tumor cells and HLA appropriate primary human cell lines representing a range of tissues, the in vitro pre-clinical package can be predictive of in vivo clinical observations. A first ImmTAC, IMCgp100, has entered phase I/IIa clinical trials for patients with advanced melanoma. The drug is well tolerated and many patients show tumor shrinkage after the first dose of ImmTAC with tumor shrinkage improving with each dose. Emerging data demonstrate durable partial responses in three patients and a complete response in a fourth patient.

Phase 2 study of the pan-isoform PI3 kinase inhibitor BKM120 in metastatic urothelial carcinoma patients.

324 Background: PI3 kinase (PI3K) pathway alterations are found in 39% of urothelial carcinoma (UC) (TCGA). Prior reports have shown significant responses in metastatic UC patients (pts) whose tumors harbor PI3K pathway alterations treated with mTOR inhibitors, providing a rationale to investigate BKM120 in mUC. Methods: This phase II study enrolled mUC pts progressing on platinum-based chemotherapy (up to 4 prior agents). The primary and secondary endpoints were proportion of pts progression-free at 2 months and response rate (RR) by Response Criteria in Solid Tumors (RECIST) v1.1, respectively. A Simon 2-stage design was used to discriminate between a 2 month PFS rate of &lt;60% (at which point the trial would be halted) vs. &gt;80%. Pts received 100 mg drug once daily. To identify predictors of response/resistance to BKM120, targeted exon capture sequencing was performed to define the mutation status of PIK3CA, PTEN, AKT1, TSC1, and additional genes within tumors from all treated pts. Results: 13 of 15 enrolled pts were eligible for the primary endpoint. Median age was 65 (53-82). Pts had received an average of 3 agents (2-4) before enrollment. The median progression-free survival (PFS) was 2.77 months (95% CI: 1.83-3.71) with 6 pts displaying stable disease (SD) and 1 partial response (PR) at 2 months (PFS rate 54%). Sequencing identified 2 pts with PIK3CA mutations (E542K, H1047R) who experienced progression as best RECIST response. Tumor from the pt with a 16 month PR harbored a TSC1 R500* nonsense mutation. 1 pt with SD lasting 3.7 months had a TSC1 L330fs truncation. Conclusions: While BKM120 therapy did not display a significant improvement in 2-month PFS rate compared to standard chemotherapy in the second-line setting, 2 pts, one with a durable PR and one with SD, had tumors with inactivating mutations in TSC1. Based upon these results, an expansion cohort is accruing in which select mUC pts whose tumors harbor PI3K pathway alterations receive BKM120. Clinical trial information: NCT01551030.

Phase II clinical trial of low-dose interleukin-2, interferon-alpha, and low-dose tegafur uracil therapy for advanced renal cell cancer.

508 Background: The objective of this trial was to evaluate the efficacy and safety of immunochemotherapy with very low-dose interleukin-2, interferon-alpha and tegafur uracil (IAT therapy) in treatment naïve metastatic renal cell carcinoma (RCC) patients with pulmonary metastasis only. Methods: Previously untreated metastatic renal cell cancer patients only with pulmonary metastasis were enrolled in this multicenter, open-label, single arm, phase II trial. Eligibility criteria included ECOG performance status (PS) 0-2, low or intermediate risk per MSKCC score, and adequate organ function. The primary endpoint was the overall response rate (ORR) per RECIST v1.1. Secondary endpoints were time to progression (TTP), response duration, overall survival (OS), ECOGPS and safety. Safety was assessed by CTCAE, v4.0. Low dose (0.7-2.1 MIU/ day) IL-2 was administered intravenously in the first five days of the first and third week. IFN-alpha (500 MIU/day) was administered 3 times per week in week 2. From 4th to 7th weeks, patients received IFN- alpha 3 times per week and 100 mg tegafur uracil t.i.d. Results: Twenty-eight eligible patients were enrolled from Apr 2009 through Dec 2013. Twenty-one patients were evaluable for ORR. Three patients had partial response (PR) 11 stable disease (SD), and 7 progressive disease (PD). ORR was 14.4% and median duration of PR was 18.0 months. TTP and OS were not reached to median and 3-year OS rate was 76.3%. Twenty-seven patients (96.4%) had an ECOGPS of 0 and 1 (3.6%) had PS of 1. Three patients experienced exacerbation in PS (PS 0 to 1). The most common adverse events (AEs) were elevation of ALT (35.7%) and fever (32.1%). AEs grade 3 included rash (14.3%), depression (3.2%), syncope (3.2%), fever (3.2%), elevation of ALT (3.2%). Four patients discontinued therapy at the time of ORR analysis due to AEs (3 rash, 1 depression). Conclusions: IAT therapy for RCC patients with only pulmonary metastasis is safe and appears to have clinical benefit as reflected by ORR rate and long OS. Clinical trial information: 00002222.

Further Evolution of Metronomic Therapy Extended to 28 Days (Metro28) for Relapsed Refractory Multiple Myeloma (RRMM)

Despite the increasing availability of novel agents for RRMM, many patients run out of treatment options due to disease refractoriness and/or progressive toxicities, both hematological (cytopenia) and non-hematological (cachexia, asthenia, renal and cardiopulmonary).Patients who are refractory to both proteasome inhibitors and immunomodulatory agents (IMIDs) carry an ominous prognosis with a median overall survival (OS) of 9 months (Leukemia, Kumar 2013). We previously reported on the efficacy and toxicity profiles of a metronomically scheduled chemotherapy regimen administered over the course of 16 days (Haematologica, Papanikolaou 2014). Encouraged by the results of that treatment, we have since modified metronomic chemotherapy to cover a 28-day period (metro28). The regimen consisted largely of bortezomib 1.0mg/m2 on days 1, 4, 7, 10, 13,16,19, 22,25,28; along with dexamethasone 12mg on days 1-4, 7-10, 13-16, 19-22, 25-28; thalidomide 100mg days 1-28, continuous 28 day infusion of doxorubicin 1.0mg/m2 (0.5mg/m2 for Ejection Fraction <40%) and cis-platinum 1.0mg/m2 (0.5mg/m2 for creatinine >2mg/dL), with the addition of arsenic trioxide (ATO) at 0.1mg/kg on each day after bortezomib; and lately vincristine (VCR) at 0.07mg daily dose by continuous infusion for 28 days. Patient characteristics included age >65yr, 46%; female, 33%; cytogenetic abnormalities at any time prior to therapy (CA), 86%; Gene Expression Profile (GEP) 70-defined high risk, 44%. The median number of prior therapies was 8 (1-64), prior transplants, 83% (1, 2, >=3), 20%, 32%, 31%; prior exposure to novel agents including Carfilzomib/Pomalidomide was 81%. Thrombocytopenia prior to treatment was present in 75% including thrombocytopenia <50,000/uL in 15%. Clinical outcomes are depicted in Figure 1. At a median follow up of 8.1 months, the median number of metro 28 cycles administered was 1 (1-5), with 37% achieving a partial response and median OS not yet reached. Interestingly, the 6 month - partial response duration estimate for the patients achieving PR was 53% (Figure 1A), while the one year OS estimate for all patients receiving metro 28 was 59% (Figure 1B). Prognostic factors that held statistical significance in univariate analysis for overall survival were albumin <3.5 g/dl (HR 2.56, P=0.009), beta-2-microglobulin (B2M) ≥3.5 mg/L (HR 3.03, P=0.003), LDH≥ 190 U/L (HR 2.81, P=0.003), GEP-70 High Risk (HR 2.32, P=0.048), GEP-5 High Risk (HR 5.75, P<0.001) (Figure 1C) and GEP PR subgroup designation (HR 3.71, P=0.003). In multivariate analysis, albumin < 3.5 g/dL (HR 2.81, P=0.035), B2M≥ 3.5 mg/L (HR 3.4, P=0.017), GEP PR subgroup (HR 3.8, P=0.012), and GEP-5 High Risk (HR 8.58, P<0.001) (Figure 1C) achieved statistical significance. The majority of cycles administered in the patient population were done in the outpatient setting (81%), while secondary admissions due to regimen toxicity occurred in 36% of the cycles administered. Grade 3 & 4 neutropenia and thrombocytopenia within 3 months from the start of the metronomic treatment were evident in 64% and 78% respectively of the cases. Treatment related mortality was 2%, due to one instance each of grade 5 infection and cerebrovascular event. In conclusion 28 day metronomic therapy is a feasible treatment with acceptable toxicity and encouraging preliminary results both in terms of ORR and OS for RRMM.Table 1:Patient characteristics at start of Metro28 therapyFactorn/N (%)Age >= 65 yr56/122 (46%)IgA Isotype28/110 (25%)Female40/122 (33%)White108/122 (89%)Albumin < 3.5 g/dL47/122 (39%)B2M >= 3.5 mg/L46/93 (49%)B2M > 5.5 mg/L26/93 (28%)CRP >= 8 mg/L54/122 (44%)Creatinine >= 2 mg/dL15/122 (12%)Hb < 10 g/dL57/122 (47%)LDH >= 190 U/L36/121 (30%)Platelet Count < 150 x 10^9/L92/122 (75%)Cytogenetic abnormalities105/122 (86%)CA within 1 year of therapy84/121 (69%)CA within 90 days of therapy65/119 (55%)New Kit GEP Sample91/91 (100%)GEP 70 High Risk40/91 (44%)GEP 5 High Risk39/91 (43%)GEP CD-1 subgroup5/91 (5%)GEP CD-2 subgroup17/91 (19%)GEP HY subgroup14/91 (15%)GEP LB subgroup6/91 (7%)GEP MF subgroup9/91 (10%)GEP MS subgroup9/91 (10%)GEP PR subgroup31/91 (34%)GEP proliferation index >= 1028/91 (31%)GEP centrosome index >= 326/91 (29%)n/N (%): n- Number with factor, N- Number with valid data for factor ND: No valid observations for factor [Display omitted] [Display omitted] [Display omitted] DisclosuresZangari:Norvartis: Membership on an entity’s Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. van Rhee:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Morgan:Celgene Corp: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Myeloma UK: Membership on an entity’s Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity’s Board of Directors or advisory committees; The Binding Site: Membership on an entity’s Board of Directors or advisory committees; MMRF: Membership on an entity’s Board of Directors or advisory committees.

IT-02 * INITIATION OF CLINICAL STUDIES WITH SL-701, A SYNTHETIC MULTI-PEPTIDE VACCINE WITH ENHANCED IMMUNOSTIMULATORY PROPERTIES TARGETING MULTIPLE GLIOMA-ASSOCIATED ANTIGENS, IN ADULTS WITH FIRST RECURRENCE OF GLIOBLASTOMA

Immune targeting presents an important therapeutic approach in glioblastoma (GBM). The SL-701 vaccine, a synthetic multi-peptide designed to induce maximal activation of the immune system against key targets in gliomas involving adults and children, demonstrated tumor regression and durable complete and partial responses when administered in combination with poly:ICLC in investigator-sponsored Phase 1/2 trials in adults with GBM and children with high- grade glioma and diffuse intrinsic pontine glioma (Okada et al., JCO, 29(3):330-6 2011; Pollack et al., JCO 2014 in press). We present an optimized version of this therapy for enhanced immune stimulation with the addition of a synthetic, highly immunogenic mutant to target survivin, a member of the inhibitor of apoptosis family of proteins that is overexpressed in tumors. Other immunogenic mutant peptides in SL-701 target interleukin-13 receptor alpha-2 (IL-13Rα2), which has also been constructed with an amino acid substitution to enhance immunostimulatory activity, and ephrin A2 (EphA2). Most glioma cell lines and primary tumor tissues from patients studied to date express 2 or 3 of these targets. Additionally, target expression was seen on cancer stem cells (CSCs) of GBM. Along with SL-701's well-selected peptide constituents, the immunostimulants GM-CSF and imiquimod, which activate multiple arms of the immune system, will be co-administered to further augment the immune response. Treatment will be delivered as a subcutaneous injection every 2 weeks for 6 months and every 28 days thereafter. This optimized version of SL-701 is now entering a multicenter clinical trial for adult patients with first recurrence GBM with the primary endpoints of overall response rate and overall survival.

Predicting success in regulatory approval from Phase I results.

Drug development in oncology is resource intensive and has a high failure rate. In this exploratory analysis, we aimed to identify the characteristics and outcomes of published Phase I studies associated with future Food and Drug Administration (FDA) approval. Phase I studies of approved and non-approved anticancer agents between 2000 and 2013 were retrospectively examined. Fisher's exact and chi-squared tests were used to compare the potential predictive measures. Phase I studies of 88 anticancer agents (54 approved and 34 non-approved by the FDA), treating a total of 4,423 subjects, were examined. The median number of patients in Phase I trials of approved and non-approved agents was 44.5 and 32, respectively. A total of 423 subjects (86 reporting studies) had a complete responses, and 342 subjects (80 reporting studies) had a partial responses (PR). A higher number of PR (P < 0.001), PR rate (P = 0.003) and longer PR duration (P = 0.001) were predictive of regulatory success. These preliminary findings indicate that objective responses in Phase I trials may have predictive value for later regulatory approval.