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We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined. The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT). No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients. ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors. NCT01598129 . Registered 19/04/2012

BACKGROUND Two randomized, double-blind trials have compared tamoxifen 20 mg daily and the selective, nonsteroidal aromatase inhibitor anastrozole 1 mg daily as first-line therapy for advanced breast carcinoma (ABC) in postmenopausal women. The trials were prospectively designed to allow for combined data analyses. METHODS The combined study population included 1021 postmenopausal women (median age, 67 years [range, 30–92]) with ABC whose tumors were either estrogen and/or progesterone receptor positive or of unknown receptor status. Primary endpoints were time to progression (TTP), objective response, and tolerability. RESULTS At a median duration of follow-up of 18.2 months, anastrozole was at least equivalent to tamoxifen in terms of median TTP (8.5 and 7.0 months, respectively; estimated hazard ratio [tamoxifen relative to anastrozole], 1.13 [lower 95% confidence level, 1.00]). In a retrospective subgroup analysis, anastrozole was superior to tamoxifen with respect to TTP (median values of 10.7 and 6.4 months for anastrozole and tamoxifen, respectively, two-sided P = 0.022) in patients with estrogen and/or progesterone receptor positive tumors (60% of combined trial population). In terms of objective response, 29.0% of anastrozole and 27.1% of tamoxifen patients achieved either a complete response (CR) or a partial response (PR). Clinical benefit (CR + PR + stabilization of ≥ 24 weeks) rates were 57.1% and 52.0% for anastrozole and tamoxifen, respectively. Both anastrozole and tamoxifen were well tolerated. Anastrozole led to significantly fewer venous thromboembolic (P = 0.043; not adjusted for multiple comparisons) events, and vaginal bleeding was reported in fewer patients treated with anastrozole than with tamoxifen. CONCLUSIONS In postmenopausal women with hormonally sensitive ABC, anastrozole should be considered as the new standard first-line treatment. Cancer 2001;92:2247–58. © 2001 American Cancer Society.

Background: Although smoking increases risk for many tumor types, no malignancy is more closely linked to tobacco exposure than small cell lung cancer (SCLC); 90% of SCLC patients are smokers. Carcinogenic compounds in cigarettes increase cancer susceptibility due to formation of DNA adducts, leading to oncogenic mutations. Etoposide in combination with cisplatin or carboplatin is the standard chemotherapy for SCLC. However, most SCLC patients eventually die of chemotherapy-refractory disease. Mutation in the tumor suppressor gene TP53 is one of the main causes for resistance, and occurs in more than 70% of SCLC patients (http://p53.free.fr). APR-246 (PRIMA-1MET) is the first clinical-stage small molecule that reactivates mutant p53 by inducing its wild-type conformation triggering apoptosis. It has been tested in a First in Human clinical trial in hematological malignancies with encouraging results (Lehmann et al. J Clin Oncol 30, 2012), and a Phase Ib/II study in combination with platinum-based therapy in recurrent ovarian cancer is ongoing (AACR abstract #CT204, 2015). We have previously observed strong synergy with APR-246 and platinum compounds in TP53-mutant drug-resistant ovarian cancer cells (Mohell et al. Cell Death and Disease 6, 2015). The aim of the present study was to investigate whether APR-246 synergizes with standard chemotherapy in SCLC cells carrying smoking-associated and/or lung cancer-specific TP53 mutations. Methods: Cell viability was tested using CellTiter-Glo assay, TP53 status with Sanger sequencing and single strand conformation analysis, and p53 protein level with Western blotting. Combination Index (CI) was calculated according to Additive model. Results: We observed synergistic (CIT transversion) and/or lung cancer specific homozygous TP53 mutations, including NCI-H2195 (V157F, 4.3% of all SCLC tumors), NCI-H1048 (R273C, 1.78%) and NCI-H889 (C242S, 1.07%). Synergy was also observed in H196 cells with hotspot R175H mutation (2.14%), while additive effect (CI = 0.8-1.2) was found in NCI-H1882 (R273L, 1.78%) and NCI-H187 (S241C, 0.36%) cells. Synergy was also observed with etoposide in NCI-H2195 cells. Moreover, APR-246 sensitized the NCI-H2195 cells to cisplatin; the IC50 value decreased about 2-fold at clinically relevant concentration of APR-246. All tested SCLC cell lines had medium or high level of p53. Further studies with other conventional drugs are ongoing. Conclusions: Treatment with APR-246 in combination with cisplatin or etoposide resulted in synergy or strong synergy in SCLC cells carrying lung cancer-specific and/or smoking-related TP53 mutations. Our results suggest that combination treatment with APR-246 and standard chemotherapy can provide significantly improved treatment of TP53-mutant SCLC. Citation Format: Nina Mohell, Åsa Fransson, Jessica Alfredsson, Mikael von Euler, Ulf Björklund, Lars Abrahmsen. Synergistic effect with APR-246 and standard chemotherapy in small cell lung cancer cells carrying smoking-associated TP53 mutations. [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 270.

5571Background: P53 is ubiquitously mutated in HGSOC. APR-246 is a novel agent which stabilises mutant P53 in the wild-type conformation, increasing cancer cell chemo-sensitivity. Our aim was to es...

APR-246 (PRIMA-1MET) is the first clinical-stage compound that reactivates mutant p53. This phase Ib part of a proof of concept study aims to determine the recommended phase II dose (RP2D) of APR-246 in combination with carboplatin and pegylated liposomal doxorubicin (PLD) in platinum sensitive High Grade Serous Ovarian Cancer (HGSOC). Despite high response rates from carboplatin in combination with paclitaxel in first-line treatment of ovarian cancer, most patients relapse and develop resistance. Partially platinum sensitive patients relapse between 6 and 24 months and are commonly treated with second -line carboplatin and PLD (Pujade-Lauraine et al. JCO, 2010). The mechanisms of platinum resistance are multifactorial; two of the main causes are mutations in p53 and increased levels of intracellular glutathione. Like the analog PRIMA-1, APR-246 is a pro-drug that is converted to the active form MQ, which restores wild type conformation to mutant p53 (Lambert et al. Cancer Cell, 2009). In addition, APR-246 has been shown in vitro to reduce glutathione levels, resensitize cancer cells to platinum drugs, and induce ROS levels and ER stress (Mohell et al. Abstract #1801, AACR 2014; Lambert et al. Oncogene, 2010). In the first-in-human phase Ia study, APR-246 monotherapy was found to have a satisfactory safety and pharmacokinetic profile allowing it to be combined with full dose chemotherapy (Lehmann et al., JCO, 2012). The ongoing phase Ib/II study is enrolling patients with recurrent platinum sensitive HGSOC with positive p53 staining on immunohistochemistry. The phase Ib study has a 3+3 dose escalation design with 3 planned dose levels. APR-246 is administered as a 6h i.v. infusion on 4 consecutive days every 4 weeks. On day 4, APR-246 is given concomitantly with carboplatin AUC 5 and PLD 30 mg/m2. In the phase II part, 164 patients will be randomized to standard chemotherapy with or without APR-246. To date patients have been enrolled to all 3 dose cohorts. One DLT of ruptured diverticulum occurred at the 2nd dose level. No new safety concerns have emerged. The pharmacokinetic profile has not indicated any interaction between APR-246 and the chemotherapy. The first 3 patients have completed their therapy and are now in follow up. All 3 had partial response (PR) by RECIST 1.1 and 2/2 evaluable also had PR by GCIC. In conclusion, early results from the ongoing clinical study are encouraging and support the continued development of APR-246 in the phase II part of the study comparing platinum based standard chemotherapy with or without APR-246 in patients with HGSOC with mutant p53. Preliminary results from all three dose levels and the RP2D will be presented at the meeting. Citation Format: Mikael von Euler, Klas G. Wiman, Hani Gabra, James D. Brenton, Bristi Basu, Ignace Vergote, Charlie Gourley, Austin Smith, Jessica Alfredsson, Nina Mohell, John A. Green. Preliminary results from PiSARRO, a phase Ib/II study of APR-246, a mutant p53 reactivating small molecule, in combination with standard chemotherapy in platinum-sensitive ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT204. doi:10.1158/1538-7445.AM2015-CT204

Background: Platinum compounds have been used as first-line treatment for many solid tumors including non small cell (NSCLC) and small cell (SCLC) lung cancer. However, patients with lung cancer often develop resistance to platinum compounds and eventually die of chemotherapy refractory disease. Mutation in the tumor suppressor protein p53 is common in lung cancer, ranging from 33% in adenocarcinomas to 70% in SCLC (The p53 website, http://p53.free.fr), and is one of the main causes for resistance to chemotherapy. APR-246 (PRIMA-1MET) is the first compound in clinical development that reactivates mutant p53 by inducing its wild type conformation thus triggering apoptosis (Lambert et al. Cancer Cell 15, 2009). APR-246 has yielded promising results in a first-in-human clinical trial in patients with hematological malignancies and prostate cancer (Lehmann et al. J Clin Oncol 30, 2012), and a Phase Ib/II study in combination with platinum-based therapy in ovarian cancer is ongoing. Previously we have shown strong synergy with APR-246 and platinum compounds in p53-mutant drug-resistant ovarian cancer cells (AACR abstract # 3448, 2013). Moreover, APR-246 completely restored the sensitivity of cisplatin to resistant p53-mutant ovarian cancer cells (AACR abstract #1801, 2014). The aim of the current study was to investigate whether strong synergistic effect can also be observed in p53-mutant lung cancer cells. Methods: Cell viability was determined with FMCA or Cell Titer-Glo assay, p53 gene status by Sanger sequencing and single strand conformation analysis, and p53 protein expression by Western blotting. Combination Index (CI) was calculated according to Additive model. Results: We observed strong synergistic effect (CI Citation Format: Nina Mohell, Åsa Fransson, Jessica Alfredsson, Mikael von Euler, Ulf Björklund, Lars Abrahmsen. Strong synergistic effects with APR-246 and cisplatin in p53-mutant lung cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2523. doi:10.1158/1538-7445.AM2015-2523

3085 Background: Clinical studies consistently show how adenovirus, unlike other viral vectors, can both prime and boost immune responses. Consequently, adenovirus is used to develop vaccines again...

TPS5605 Background: p53 mutations are associated with increased chemoresistance. APR-246 is a small molecule that restores mutant p53 to wild type conformation and function (Lambert et al., Cancer ...

e13551^ Background: Most of the protein kinase inhibitors (PKIs) have very challenging solubility properties and many products are suffering from pH dependent absorption, food effect and high varia...

e13035 Background: Following preclinical testing CGTG-102, a 5/3 chimeric oncolytic adenovirus armed with human GMCSF, has been used to treat 115 refractory cancer patients. Methods: Eligibility criteria included refractory advanced solid tumors, no major organ deficiencies and written informed consent. Patients were treated with either a single treatment or serial treatments with one or more viruses. Intra tumoral administration was performed under ultrasound guidance. The initial dose, 8 x 1010 Viral Particles (VP), was based on published safety results and preclinical testing and escalated in later patients. A routinely tolerated dose of 3 x 1011 VP was deemed optimal and is the target dose for clinical development. To reduce regulatory T-cells, low-dose cyclophosphamide 50 mg/day was given. Adverse Reactions (AR) were scored according to CTCAE 3.0. Imaging was done by CT before and ~2 months after treatment. Response was scored according to RECIST 1.1, including injected and non-injected lesions. Decrease not fulfilling PR was scored as minor response (MR). Results: The most common ARs were pain (82%), fever (81%), fatigue (79%), nausea (54%) and hemoglobin decrease (48%). Pain is mostly tumor pain or pain in the injected tumor, which may be causally related to the MOA of the therapy. Most ARs were G1 or G2; 6 were G4: 2 Hb decrease, 2 pulmonary embolism and single reports of thrombocytopenia and pericardial effusion, most probably due to the underlying disease.Imaging was performed when clinically useful. 65/115 are evaluable by imaging: 3% PR, 11% MR, 40% SD and 46% PD. Best results were obtained in Breast Cancer, Melanoma, Soft Tissue Sarcoma, Mesothelioma and Ovarian Cancer. Median survival in this heavily pre-treated refractory population is 164d, 95% CI 122d – 206d. Mean survival is 281d reflecting that approx. 30% survive more than 300d and 15% up to 600d. A wide range of samples are being analyzed to further characterize the viral and immunological aspects of the therapy. Conclusions: CGTG-102 is a novel oncolytic adenovirus with good safety profile and encouraging signs of efficacy. Formal clinical studies are underway in several tumor types in both US and EU.

Advanced tumors are often immunosuppressive. Intratumoral administration of adenovirus activates Toll-like receptor signalling leading to production of pro-inflammatory cytokines and activation of the innate immune system. Oncolytic adenovirus causes immunogenic cancer cell death and creates a danger signal at tumors, thus undermining immunological tolerance towards tumors. The release of tumor antigens from dying cancer cells results in priming of a potent anti-tumor immune response. This effect may be enhanced by the local production of immunostimulatory molecules coded by the virus. We present results of gene expression analysis of tumors from a Phase I study with ONCOS-102, an oncolytic adenovirus coding for GMCSF, in 12 patients with refractory solid tumors. A total of 9 intratumoral injections of ONCOS-102 were given to each patient. Biopsies were collected at baseline and 1 and 2 months after treatment initiation. RNA was extracted from fresh-frozen biopsies using standard methods. Gene expression profiling was carried out using the Illumina BeadChip platform. Data was normalized by quantile method, probes presenting the same genes were averaged, and the batch effects were adjusted using ComBat pipeline, as implemented in Chipster (http://chipster.csc.fi/). Finally, log2 fold-changes were computed by subtracting baseline data from after treatment data. Network and pathway analyses were conducted through the use of IPA (Ingenuity ®Systems, http://www.ingenuity.com). A cutoff value of 2-fold expression change was used to filter differentially expressed genes and run core analysis to identify underlying signaling networks and deregulated molecules. A significant enrichment of genes involved in immune cell trafficking, inflammatory response and antigen presentation were detected post treatment. A mesothelioma patient showed a prominent post-treatment induction of MAGE3-specific CD8+ T-cells in peripheral blood in IFNγ ELISPOT. Furthermore, a late decrease in metabolic activity was observed in PET imaging 7.5 months after treatment initiation during the follow-up period, measured as a 47% decrease in total lesion glycolysis in comparison to the imaging at 6 months. In the same patient, upstream regulators driving differentially expressed genes detected in the post treatment biopsy included cytokines (INFG, TNF, IL1B, CCL2, CXCL10, IL-17A, CD40LG), enzymes (FN1, NOS2, PTGS2, PARP9), growth factors (BMP2, LEP), kinases (CHUK, CRKL, IKBKB, IKBKG, ITK, STK11, SYK), transcriptional regulators (IRF1, NFATC2, NFKBIA, STAT1, STAT3, ZEB1, RELA), and transmembrane receptors (B2M, CD40, IL6R, TLR2-4, TNFSF1B). Likely, these events collectively induced a higher CD8+ mediated cytotoxic T cell response (GZMB, PRF1) post treatment. Detailed analysis per patient will be presented at the meeting.