Early Signs Of Activity Research Articles

Abstract 837: Preclinical development of ELU001: A folate receptor alpha (FRα)-targeted C’Dot drug conjugate (CDC) for the treatment of brain metastases

Abstract Antibody-drug conjugates (ADCs) exhibit limited efficacy against brain malignancies due to their inability to cross the blood-brain barrier (BBB) and penetrate into solid tumors. In clinical imaging studies C’Dots readily crossed tumor-disrupted BBB and penetrated across/localized in tumors in the brain avoiding healthy brain. CDCs are ultra-small (6-7 nm) nanoparticles with a silica core coated by short polyethylene glycol chains conjugated to up to 80 small payload and targeting moieties, creating highly potent and avid agents. CDCs’ small size mediates rapid renal clearance leading to limited exposure to healthy tissues. ELU001 is a potent anti-FRα CDC with an average of 21 exatecan topoisomerase-1 inhibitor payload molecules and 13 folic acid targeting molecules on its surface. ELU001 is currently in a dose escalation trial in patients with systemic solid tumor indications that have the potential to overexpress FRα. Early signs of activity with a manageable safety profile have been seen across antigen expression levels. ELU001 exhibits in vitro potency in the sub/low nanomolar range against cancer cell lines that express 3+, 2+ or 1+ levels of FRα. In studies performed in immunodeficient mice bearing intracranial NCI-H2228-luc bioluminescent non-small cell lung cancer tumors, ELU001 was observed to penetrate across disrupted BBB and localize in tumors. Microscopic analysis revealed that ELU001 distributed throughout the tumors but not into the healthy brain. Treatment with a single cycle of ELU001 Q3Dx3 in mice bearing either early (Day 7) or late (Day 14) brain tumors was well tolerated and resulted in significant reduction in tumor burden measured by bioluminescence as well as a prolonged survival benefit. Retreatment of these animals resulted in an additional decrease in tumor burden. These results suggest that ELU001 may have promise for the treatment of metastatic brain tumors that are difficult to treat with currently available agents. Citation Format: Gregory P. Adams, Tin Khor, Feng Chen, Kai Ma, Marion Scocca, Aranapakam Venkatesan, Cathy Reddick, Mary Hilgart, Thomas Gardinier, Fei Wu, Melik Turker, Peiming Chen, Vaibhav Patel, Eliel Bayever. Preclinical development of ELU001: A folate receptor alpha (FRα)-targeted C’Dot drug conjugate (CDC) for the treatment of brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 837.

Abstract CT041: Monotherapy dose escalation of davoceticept (ALPN-202), a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies (NEON-1)

Abstract Background: Strong preclinical rationale has emerged for combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly CD28, a critical T cell costimulatory molecule recognized as a key target of checkpoint inhibition. Davoceticept (ALPN-202) is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in vitro and in in vivo tumor models, while demonstrating favorable preclinical safety. Methods: This is a first-in-human, cohort-based, open-label dose escalation and expansion study of davoceticept in adults with advanced solid tumors or lymphoma (NCT04186637). Patients with cancers refractory to standard therapies (including approved CPIs), or cancers without available standard or curative therapy are eligible. After two single-subject cohorts, a standard 3+3 dose escalation has been implemented with two dose schedules in parallel, Q1W and Q3W. Objectives include evaluation of safety and tolerability, PK, PD and preliminary anticancer activity. Disease assessments are evaluated by RECIST v1.1 for solid tumors. A prior presentation discussed the initial first 5 cohorts of the Q1W schedule; this presentation includes the remainder of dose escalation, including the Q3W schedule. Results: As of December 2021, 57 adults with various advanced solid tumors, most commonly colorectal and pancreatic, received davoceticept monotherapy, which was well tolerated through 10 mg/kg Q3W. Davoceticept demonstrated dose-dependent PK and target saturation. Immune-related adverse events (irAEs), occurred in 20/54 (35%), mostly involving the skin, endocrine and gastrointestinal systems. All but 2 of the irAE were grade 1-2. One DLT, chronic active gastritis grade 3, was observed at 3 mg/kg Q3W. Among 47 evaluable, unconfirmed partial responses were observed in 2 (colorectal carcinoma and renal cell carcinoma). Stable disease, defined as first scan at 6 weeks, was observed in 22; 9 (41%) demonstrated tumor volume reduction, 2 (9%) demonstrated SD for > 6 months, and 1 has an ongoing SD at 8 months. At doses above 0.1 mg/kg, pharmacodynamic ex vivo analyses demonstrated agonistic engagement of CD28 on T cells, and flow cytometry demonstrated increased circulating activated (ICOS+) and proliferating (Ki-67+) T cells, increased central memory T cells, and reduced regulatory T cells, consistent with active CD28 engagement. Conclusion: First-in-human dose escalation with davoceticept was well tolerated at doses capable of engaging CD28 costimulation in vivo, with early signs of activity in a largely treatment-refractory, non-immunogenic tumor population. These findings suggest a potential additive benefit of combining CD28 agonism with checkpoint inhibition and identify biologically active dose regimens of davoceticept for subsequent single agent development, and demonstrate further rationale for combination development. Expansion cohorts, including cutaneous melanoma and PD-L1-positive cancers, are planned. Citation Format: Michael Millward, Justin C. Moser, Diwakar Davar, Mark Voskoboynik, Nehal J. Lakhani, Rachel E. Sanborn, Jaspreet Grewal, Ajita Narayan, Mario Sznol, Keren Schieber, Hany Zayed, Christine Dela Cruz, Graciela Perez, Stanford L. Peng. Monotherapy dose escalation of davoceticept (ALPN-202), a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies (NEON-1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT041.

Dose escalation of davoceticept, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies (NEON-1).

2560 Background: Strong preclinical rationale supports combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly of CD28, a critical T cell costimulatory molecule recognized as a key target of checkpoint inhibition. Davoceticept (ALPN-202) is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in multiple tumor models in vitro and in vivo, while demonstrating favorable preclinical safety. Methods: This is an open-label dose escalation and expansion study of davoceticept in adults with advanced solid tumors or lymphoma (NCT04186637). Patients with cancers refractory to standard therapies including CPIs, or cancers without available standard or curative therapy are eligible. Dose escalation studied two dose schedules, Q1W and Q3W. Objectives include safety and tolerability, PK, PD and preliminary anticancer activity. Disease assessments are evaluated by RECIST v1.1 for solid tumors. A prior presentation discussed the first 5 cohorts of the Q1W schedule; this presentation updates progress in dose escalation, including the Q3W schedule. Results: As of January 2022, 57 adults with various advanced solid tumors, most commonly colorectal and pancreatic, received davoceticept monotherapy, which was well tolerated through 10 mg/kg Q3W. It demonstrated dose-dependent PK and target saturation. Immune-related AEs (irAEs), occurred in 20/57 (35%), mostly of the skin, endocrine and gastrointestinal systems. All but 4 of the irAE were grade 1-2. Only one DLT (chronic active gastritis grade 3) was observed at 3 mg/kg Q3W. Among 48 evaluable patients, unconfirmed partial responses were observed in 2 (colorectal and renal cell). Stable disease, at first scan at 6 weeks, was observed in 23 (48%); 11 (23%) demonstrated volume reduction (target lesion ΔSLD < 0%); 2 had SD for > 6 months, and 1 had an ongoing SD at 8 months. At doses above 0.1 mg/kg, ex vivo analyses showed agonism of T cell CD28, and flow cytometry demonstrated increased circulating activated (ICOS+), proliferating (Ki-67+) and central memory T cells, and reduced regulatory T cells, consistent with CD28 engagement. Conclusions: Davoceticept was well tolerated at doses capable of engaging CD28 costimulation in vivo, with early signs of activity and peripheral immune activation in a largely treatment-refractory, non-immunogenic tumor population. These findings support an additive benefit of combining CD28 agonism with checkpoint inhibition and identify biologically active dose regimens of davoceticept for subsequent single agent development, and provide further rationale for combination study. Expansion cohorts, including cutaneous melanoma and PD-L1-positive cancers, are planned, and a combination study with pembrolizumab has initiated (NCT04920383). Clinical trial information: NCT04186637.

Abstract 2925: Safety and efficacy of EZH2 and BRD4 dual targeting in EZH2Y641mut germinal centre-derived lymphoma

Abstract A significant proportion of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) patients harbor a gain-of-function, heterozygous somatic mutations of the methyltransferase gene EZH2. Despite acceptable safety profile and early signs of activity in clinical trials, single agent treatment with EZH2 inhibitors is unlikely to be curative in aggressive lymphomas. In an effort to established novel rational combinations, we have evaluated the activity and mechanism of action of the EZH2 small molecule inhibitor CPI169 as single agent and in combination with BET bromodomain inhibition, using preclinical models of DLBCL and FL with distinct EZH2 mutational status. CPI169 anti-tumor activity and specificity was assessed in vitro in 10 DLBCL and FL cell lines, including cells expressing basal or ectopic EZH2mut. Molecular bases of its activity were determined by gene expression profiling (GEP), qPCR and western blot, followed by automated exploratory data analysis. Biomarkers validation was made in vitro and in vivo, using a mouse xenotransplant model of EZH2mut DLBCL, considering both exposure to CPI169 single agent and/or combination treatment with a BRD4 inhibitor, CPI203. CPI169 induced dose-dependent proliferation blockade in EZH2mut, but not EZH2wt DLBCL and FL cell lines, independently of EZH2 expression level or basal methyltransferase activity. Loss of H3K27me3 mark upon CPI169 treatment was associated with upregulation of gene sets related to G1 cell cycle blockade, mTOR and P53 pathways, and MYC signaling. Accordingly, combination with the MYC-interfering drug, BET inhibitor CPI203, achieved a synergistic anti-proliferating activity in EZH2 mutated cases and in mice bearing EZH2mut DLBCL tumors. Activity of EZHi/BRD4i combo was characterized by lower mitotic index, increased loss of H3K27me3 mark, in association with MYC downregulation. GEP analysis, followed by automated exploratory data analysis and validation by a siRNA screening, further identified the PI3K/AKT-regulated gene and mitosis regulator, YPEL2, and the regulator of innate-like B lymphocyte maturation, KLHL14, as crucial factors involved in the efficacy of MYC/EZH2 dual targeting. In conclusion, CPI169 shows significant activity and safety as single agent in EZH2 mutated-DLBCL and FL cases and displays synergistic interaction in vitro and in vivo with BRD4 inhibition, mediated by the modulation of a limited set of EZH2-regulated genes. Citation Format: Aranzazu Chamorro-Jorganes, Marcelo L. Ribeiro, Nuria Profitos-Peleja, Diana Reyes-Garau, Clara Recasens-Zorzo, Juan G. Valero, Marc Armengol, Patricia Perez-Galan, Ray Butler, Antonio Postigo, Francesc Bosch, Gael Roue. Safety and efficacy of EZH2 and BRD4 dual targeting in EZH2Y641mut germinal centre-derived lymphoma [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 2925.

Preliminary Results of a Phase 2a Dose Optimization Study of ASLAN003 (DHODH inhibitor) in Acute Myeloid Leukemia (AML) Patients Who Are Ineligible for Standard Therapy; Early Signs of Activity

Background:Dihydroorotate dehydrogenase (DHODH), catalyzing the ubiquinone-mediated oxidation of dihydroorotate to orotate, is the rate-limiting enzyme in the de novo synthesis of pyrimidines, and as such may control the rate of cell division. The enzyme is localised on the outer side of the inner mitochondrial membrane, and links both the electron transport chain to pyrimidine production and thus to the maintenance of cell viability. DHODH inhibitors were identified in a myeloid differentiation screen using an ER-HoxA9 GMP cell line, and ASLAN003, a novel small molecule DHODH oral inhibitor, has been found to be a potent inducer of myeloid differentiation in AML cell lines. ASLAN003 also demonstrated the ability to reduce leukemic burden and extend survival in AML xenograft models. ASLAN003 has previously been shown to exhibit a safe and tolerable profile in prior phase I studies in healthy volunteers.Methods:A multicenter, single arm phase IIA study was initiated to evaluate ASLAN003 monotherapy administered as a 28-day cycle in patients with AML who are ineligible for standard therapy. The primary objective is to determine the optimum dose of ASLAN003 in this AML cohort based on efficacy (Overall Complete Remission Rate, % of complete remission [CR] + CR with incomplete hematologic recovery [CRi]), tolerability and safety. The secondary objective is to assess the pharmacokinetics (PK) of ASLAN003 and its metabolites and to further assess the efficacy based on relapse-free survival and clinical benefit rate (CBR, % of partial remission + CR + CRi). Exploratory objectives are to examine the myeloid differentiation effects of ASLAN003 ex vivo and explore possible relationships between the clinical response and molecular profile of leukemic cells. The study contains 3 cohorts for the optimum dose determination (100 mg, 200 mg, and 300 mg once daily [QD], with planned enrollment for 6 patients for each cohort), and an additional expansion cohort with the selected optimum dose (20 patients).Results:Enrollment started in December 2017. As of 12 July 2018, 10 patients were enrolled and treated (6 in the 100 mg QD cohort and 4 in the 200 mg QD cohort). Although the data are immature, two patients to date have exhibited some evidence of clinical activity (one per cohort). A patient in the 100 mg QD cohort, with a baseline peripheral blood blast of 27%, experienced a reduction to 6% on Cycle 3 Day 10 (C3D10), coupled with an upward trend in the percentage of neutrophils (16% at baseline, 64% on C3D10). The patient had underlying chronic lung infection, but also showed suspected symptoms of differentiation syndrome (dyspnea, leukocytosis). After 126 days of ASLAN003 initiation, the patient expired due to AML related clinical deterioration. The second patient in the 200 mg QD cohort experienced a decrease in bone marrow blasts from 26% at baseline, to 12% on C2D1. Concomitantly, there was a slight decrease in peripheral blood blasts with an increase in neutrophil percentages from 7% to 51%. The patient remains on study with further efficacy data awaited. To date, the safety profile is consistent with the previous healthy volunteer studies. Treatment-related adverse events (AEs) are listed in Table 1. The most frequent treatment-related AEs include nausea (n=2, 20%) and leukocytosis (n=2, 20%). Two treatment-related Grade ≥ 3 AEs were observed (Grade 3 anaemia and Grade 3 leukocytosis). The study continues and is currently enrolling to the 200 mg cohort.Conclusion:At the date of submission, this is the first report of clinical activity of a DHODH inhibitor in AML patients. Monotherapy with ASLAN003 was well tolerated and has showed encouraging signs of clinical activity in AML patients. This study is on-going and the optimal dose for AML has not yet been determined. Safety, PK and efficacy data will be updated at the time of presentation. Clinical trial information: NCT03451084 [Display omitted] DisclosuresChng:ASLAN Pharmaceuticals: Research Funding. McHale:ASLAN Pharmaceuticals: Employment, Equity Ownership. Hsieh:ASLAN Pharmaceuticals: Employment, Equity Ownership. Shih:ASLAN Pharmaceuticals: Employment; AstraZeneca Taiwan: Employment. McIntyre:ASLAN Pharmaceuticals: Consultancy. Kwek:ASLAN Pharmaceuticals: Employment. Chang:ASLAN Pharmaceuticals: Employment. Lindmark:ASLAN Pharmaceuticals: Employment, Equity Ownership.

The OP-104 Anchor Study: A Phase 1/2 Study of Safety and Efficacy of Melflufen and Dexamethasone in Combination with Either Bortezomib or Daratumumab in Patients with Rrmm; First Report on Phase 1 Data

The OP-104 Anchor Study: A Phase 1/2 Study of Safety and Efficacy of Melflufen and Dexamethasone in Combination with Either Bortezomib or Daratumumab in Patients with Rrmm; First Report on Phase 1 Data

Phase 1 dose escalation of ZW25, a HER2-targeted bispecific antibody, in patients (pts) with HER2-expressing cancers.

1035 Background: The HER2 receptor is expressed across a range of cancers (ca) although expression and heterogeneity vary greatly within and between tumors. FDA approved HER2-targeted therapies (tx) have shown clinical benefit only in HER2 high (IHC3+ or IHC2+/FISH+) breast and gastric ca. ZW25, built on the Azymetric™ platform which utilizes unique Fc mutations to create IgG1-like bispecific antibodies, binds to the same extracellular domains of HER2 as trastuzumab (T) and pertuzumab (P) with increased binding and internalization compared to T alone. In preclinical studies ZW25 was well tolerated and active in models of HER2 low to high ca. Methods: Eligible pts (HER2 IHC 1-3+, progression after standard of care (SOC) tx, normal LVEF) were enrolled in a 3+3 dose escalation study of ZW25 (5, 10 or 15 mg/kg) IV weekly in 4 week cycles. Assessments included adverse events (AEs), LVEF, tumor response and PK. Results: 9 pts have received ZW25 at 5 (n = 3) or 10 mg/kg (n = 6); 15 mg/kg is ongoing. All pts were HER2 high (breast = 4; gastric/GEJ = 4; adnexal = 1). Prior tx included T in all pts; P and T-DM1 in 4 and lapatinib (L) in 3 of 4 breast pts. The most common AEs (all Gr 1/2) were infusion reaction (IR) (5/9), diarrhea (4/9), and fatigue (3/9), with no DLTs and one related Gr 3 AE of hypophosphatemia. The IRs occurred only with 1st dose and did not recur with prophylactic tx (primarily acetaminophen and diphenhydramine; steroids included for 2 pts). At 5 mg/kg, peak drug levels after C1D1 = ~100 ug/ml, accumulating ~50% higher by dose 4. Best response in 8 pts (1 too early): 2 PR (both breast ca with prior T, P, T-DM1, and L; 10 mg/kg, 55% and 33% target lesion decrease, respectively, after 2 cycles), 1 SD (breast ca, 5 mg/kg, ongoing after 4 cycles), and 5 PD. 5 pts currently active; includes 1 gastric pt (10 mg/kg) with PD (new nodal lesions) and clinical benefit with decrease in target lesions and CEA (33 to 1.5 ng/ml). Conclusions: ZW25 has been well tolerated with promising anti-tumor activity in pts with HER2-expressing ca progressing after SOC therapy. These early signs of activity support the therapeutic potential for bispecific antibodies using the Azymetric platform. Development of ZW25 is ongoing, including in lower HER2-expressing ca. Clinical trial information: NCT02892123.

The Drug Rediscovery Protocol (DRUP).

2547 Background: Bringing precision medicine to cancer patients remains a challenge. For many cancers, the relative contribution of tumor type, mutations or CNV to drug sensitivity remains unknown. In addition, drug access is generally limited to the labeled indication, bypassing rarer disease subgroups for which large trials are not feasible. An innovative trial that facilitates drug access, whilst systematically analyzing treatment outcomes and biomarkers, could help overcome these challenges. Methods: We designed a prospective, non randomized clinical trial in which patients with advanced cancer are treated with targeted or immunotherapy matched to their tumor profile, defined by genetic aberration, microsatellite instability (MSI) or high mutational load (HML). Upon a mandatory pre-treatment tumor biopsy for biomarker research, patients are enrolled in multiple parallel cohorts, each defined by study drug, histologic tumor type and molecular tumor profile. Efficacy is analyzed per cohort, enrolling 8 patients in stage I and 16 more in stage II if ≥1 response is observed in stage I. Study endpoints include objective tumor response (CR or PR), stable disease (SD) at 16 weeks and grade≥3 adverse events. The DRUP is registered at ClinicalTrials.gov (NCT02925234). Results: Since start of recruitment in Sep 2016, 76 patients have been submitted for review (mean per month 15, range 8-17) and 16 (21%) have started treatment in 10 different cohorts, directed at either ATM (n = 1; breast cancer), BRAF (n = 2; salivary duct carcinoma and ACUP), BRCA (n = 1; breast cancer), ERBB2 (n = 2; CRC), HML (n = 2; prostate and CRC), MSI (n = 5; CRC, GBM and urothelial carcinoma), RET (n = 1; NSCLC) or RAS-RAFwt (n = 2; SCC and sarcoma). Out of the 7 patients for whom response evaluation is available, PR (n = 2) or SD at 16 weeks (n = 1) was observed in 3 (43%). Thirteen study drugs (supplied by 6 pharmaceutical companies) are currently available, 6 more are expected soon. Conclusions: Execution of a nationwide multidrug precision oncology trial is feasible. It contributes to oncologists’ education on molecularly targeted therapies and to identification of early signs of activity in rare cancer subsets. Data sharing with similar studies such as TAPUR and CAPTUR will help to enlarge cohorts and affirm conclusions. Clinical trial information: NCT02925234.

New Targeted Agents in Endometrial Cancer: Are We Really Making Progress?

Endometrial cancer is the most common gynecological malignancy in Europe and North America. Metastatic and recurrent disease is generally incurable with poor prognosis. Recent advances in molecular profiling of endometrial cancer have elucidated four distinct molecular subtypes with different biology and prognosis which should facilitate the development of treatments tailored to disease-specific subgroups. To date, some molecular-targeted agents have shown interesting clinical activity in the recurrent setting, but no targeted therapies are approved for endometrial cancer. Novel pan-PI3K, AKT, and dual PI3K-mTOR inhibitors are being investigated with early signs of activity, but there are concerns about tolerability and toxicity in this often elderly patient population with comorbidities. The development of anti-angiogenic therapies, PARP inhibitors, and immunotherapies, alone or in combinations, appear to be promising strategies. This paper will describe the current evidence supporting the efficacy of molecular-targeted agents already tested in the treatment of metastatic and recurrent EC, and provide some insights on emerging data related to novel-targeted therapies.

Assessing End of Phase 2 Decision Criteria

The objectives of the Phase 2 stage in a drug development program are often to evaluate the safety and tolerability of different doses, select a promising dose range, and look for early signs of activity (i.e., to establish proof of concept). At the end of Phase 2 (EOP2), a decision to initiate Phase 3 studies is made that involves the commitment of considerable resources. One of the key factors in this decision is the expected efficacy and the associated predicted probability of success (PoS) in Phase 3. Making a decision based upon the PoS requires decision makers to select a benchmark (or PoS criterion) for the PoS, which if achieved would enable a “go-to-Phase 3” decision. However, appropriately choosing the criterion requires knowledge of the operating characteristics associated with the decision criteria. A key operating characteristic that a funder/sponsor requires to make such a choice is to understand the predicted conditional probability of making a go decision and subsequently failing in Phase 3. In this article, we show how such risks can be informed through the use of clinical trial simulation. We also highlight through a worked example in pancreatic cancer how this simulation exercise can help to decide between different development strategies for a specific indication. Supplementary materials for this article are available online.

Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma.

Melanoma often spreads to cutaneous or subcutaneous sites that are amenable to direct, intralesional injection. As such, developing effective injectable agents has been of considerable interest. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for the treatment of advanced melanoma. Pre-clinical studies have shown that T-VEC preferentially infects melanoma cells and exerts antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has now been assessed in Phase II and III clinical trials and has demonstrated a tolerable side-effect profile and promising efficacy, showing an improved durable response rate and a trend toward superior overall survival compared to granulocyte-macrophage colony-stimulating factor. Despite these promising results, responses have been uncommon in patients with visceral metastases. T-VEC is currently being evaluated in combination with other immune therapies (ipilimumab and pembrolizumab) with early signs of activity. In this review, we discuss the preclinical rationale, the clinical experience, and future directions for T-VEC in advanced melanoma.

A phase 1 study of weekly high dose sunitinib in patients with advanced solid tumors: Early signs of activity in non-RCC tumor types.

e13550 Background: Increased exposure to sunitinib is associated with improved outcome. Preclinical data shows promising antitumor activity of intermittent exposure to high sunitinib concentrations...

Photometry and imaging of Comet 103P/Hartley in the 2010–2011 apparition

The results of a CARA (Cometary Archive for Afρ) campaign on Comet 103P/Hartley 2 are presented. The main goal was to monitor extensively the comet during the apparition with CCD R and I imaging and photometry, as a support of EPOXI mission.The Afρ quantity showed a progressively rising ascending branch, followed by an apparent flat maximum that lasted for 2months, from about −10 to +50days from perihelion. In this period, Afρ peaked at around 100cm in R band with strong short term fluctuations between 70 and 140cm. Early signs of activity were detectable well before perihelion (about 80–90days before) and a random variability is also present in the descending branch after perihelion. Three post perihelion data points (between +55 and +61days) from the 1997–1998 apparition show a bit higher Afρ value of our observation and a similar fast variation.The average Afρ behavior, corrected for the solar phase effect, is strongly asymmetric and shows a more steeper ascending branch, approaching to perihelion.Morphology and coma asymmetry, as well as the sunward and tailward profiles are examined. An average gradient indicatively between ∼ρ−0.7 and ρ−1 is observed in the inner coma (ρ<2000km). Ten small amplitude outbursts have been detected and two ones were suspected.

Abstract C17: A phase I study of the combination of RO4929097 (RO) and cediranib (Cd) in patients with advanced solid tumors (PJC-004/NCI 8503).

Abstract Background: The NOTCH signaling pathway has been implicated in the tumorigenesis of several human cancers. Pre-clinical models have shown that deficiency of components of the NOTCH pathway results in abnormal vascular remodelling. Upregulation of NOTCH signaling has been implicated in resistance to anti-VEGF therapy, providing a rationale for the combination of RO, a gamma secretase inhibitor that disrupts NOTCH signaling, and Cd, a VEGFR-tyrosine kinase inhibitor. The primary objective of this study is to determine safety, tolerability and the recommended phase II dose (RP2D) of the combination of RO and Cd. Secondary objectives are preliminary anti-tumor efficacy, as per RECIST v1.1 measurements, as well as pharmacokinetic and pharmacodynamic studies. Methods: Adults with histologically confirmed solid malignancies for whom no effective conventional treatment is available are eligible. A standard 3+3 dose-escalation design is used. Cycle 1 is 42 days (D), where RO is given orally once daily D1–3, 8–10, 15–17, 22–24, 29–31, 36–38 and Cd is given orally once daily D22–42. Cycle 2 and onwards are 21 days, with RO given D1–3, 8–10, 15–17 and Cd given continuously D1–21. The dose-limiting toxicity (DLT) evaluation period is 42 days (cycle 1). Results: As of August 15 2011, 11 patients (pts) have been treated at two dose-levels (DL). 7 pts were treated at DL1 (RO = 10 mg; Cd =20 mg,) and 4 were treated at DL2 (RO = 20 mg; Cd = 20 mg). Pts had received a median of 3 prior lines of treatment prior to enrolment and received a median of 3 cycles on study. The most common drug related adverse events were: diarrhea (n = 9), hypertension (n = 6), nausea (n = 5), headache (n = 4), fatigue (n = 4), liver enzyme elevation (n = 3), hypophosphatemia (n = 3), anemia (n =3) and hypothyroidism (n =3). There were 2 DLTs observed: grade 3 hypertension occurred in a pt with metastatic melanoma treated at DL1 and grade 4 aspartate aminotransferase (AST) elevation in a pt with metastatic uterine leiomyosarcoma treated at DL2. Best response was stable disease in 7 pts, progressive disease in 3 and 1 pt was inevaluable. A prolonged response of over 6 cycles was observed in 3 pts (1 pt with cholangiocarcinoma withdrew consent after completing cycle 6, 1 pt with endometrial stromal sarcoma is still on study and stable after 8 cycles, 1 pt with colon cancer progressed after completing 7 cycles). Reasons for discontinuation were progressive disease in 6 pts, toxicity in 1 pt and withdrawal of consent in 1 pt. 3 pts are still on study. Conclusion: The combination of RO and Cd appears feasible; dose escalation is ongoing to establish the RP2D. Pharmacokinetic and pharmacodynamic studies to evaluate soluble markers of angiogenesis will be conducted. The combination of RO and Cd shows encouraging early signs of activity, with 3 of 11 patients achieving stable disease for at least 6 cycles. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C17.

Combination of the immunocytokine F16-IL2 with doxorubicin or paclitaxel in patients with solid tumors: Results from two phase Ib trials.

2595 Background: F16-IL2 is a tumor-targeting immunocytokine composed of the antibody fragment F16 (specific to the tumor marker A1 domain of tenascin) and of human interleukin-2 (IL2). Thorough preclinical work showed that F16-IL2 localizes selectively at tumor tissues and enhances the activity of certain anticancer drugs. In these phase Ib studies, we investigated F16-IL2 in combination with doxorubicin or paclitaxel, defining the recommended dose (RD) and assessing safety, tolerability, and early signs of activity. Methods: Cohorts of pretreated patients with progressive solid tumors received weekly administrations of 6 escalating doses of doxorubicin (up to 25mg/m2) or 8 escalating doses of paclitaxel (up to 90mg/m2), combined with F16-IL2 (up to 25 MioIU of IL2 equivalent) for a maximum of 6 months. Safety and efficacy were evaluated using CTC v3.0 and RECIST criteria. Results: 18 and 28 patients, with a median age of 63 years (37-75) and 64 years (42-79), were treated in the doxorubicin and paclitaxel combination trials, respectively. Toxicity was manageable with only few reversible G4 events, no serious unexpected adverse reactions, and no treatment related deaths. The RD was defined as 25 MioIU of F16-IL2 given in combination with 25mg/m2 doxorubicin or 90mg/m2 paclitaxel weekly. Objective responses and long-lasting disease stabilizations were observed, including 4 partial responses, 2 of which in heavily pretreated NSCLC patients and 1 still ongoing after 17 months from beginning of treatment. Among the evaluable patients treated with the paclitaxel or doxorubicin combination respectively, PFS rate at 3 months is 50% and 44% (n=24 and n=16) and 1-year survival rate is 41% and 38% (n=17 and n=13). Conclusions: 25 Mio IU of F16-IL2 combined with full-dose doxorubicin or paclitaxel can be safely and repeatedly administered weekly to patients with solid tumors, and showed early signs of clinical activity. Based on preclinical evidence, these combination regimens are being administered to breast cancer patients in phase II trials. Moreover, starting from the observed promising signs of activity, a study of F16-IL2 in lung cancer patients is being planned.

Daily administration of MGCD265 to patients with solid tumors in a dose-escalation phase I study (study 265-101).

3106 Background: MGCD265 is an orally-available tyrosine kinase inhibitor that targets Met, VEGFR-1, -2, -3, Tie-2 and Ron. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered once daily as a continuous 21-day cycle. Cohorts of 3-4 patients were enrolled per dose level, initially with dose doubling between cohorts, followed by smaller increments once grade 2 drug-related toxicity is observed. Response is assessed every 2 cycles by RECIST criteria and plasma makers (VEGF, HGF, shed Met and soluble VEGFR2) are being analyzed. Results: The first18 patients received capsules of MGCD265: 4 patients at 24 mg/m2; 3 patients at 48 mg/m2; 4 patients at 96 mg/m2; 3 patients at 150 mg/m2 and 4 patients at 300 mg/m2. Hypertension was observed in one patient at 300 mg/m2 during the first cycle of treatment. This event was considered to be a dose limiting toxicity. Grade 2 adverse events considered at least possibly related to the treatment included: hypertension, anemia, nausea and diarrhea. A tablet formulation was recently introduced at 150 mg/m2 (n=4) and at the 250 mg/m2 dose levels. To date, 5 patients have experienced stable disease. Available archived biopsies obtained prior to MGCD265 treatment from 3 of these 5 patients showed Met protein expression and autophosphorylation. Preliminary PK data indicate a Tmax of approximately 5 hours with a long half-life (∼26 hours). PK profile from tablets and capsules appears similar based on MGCD265 clinical studies. At 150 mg/m2, the steady state plasma concentration is anticipated to be in the range of the exposure at an efficacious dose in xenograft models of Met sensitive tumors. Preliminary PD analyses indicate modulation of VEGF by MGCD265. Conclusions: To date, daily oral administration of MGCD265 has been found to be well tolerated with early signs of activity and at 150 mg/m2, the human exposure is predicted to be in the range of an efficacious dose in preclinical Met sensitive models. In the absence of significant toxicity, this dose could be considered a phase II dose. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MethylGene MethylGene MethylGene MethylGene

Sorafenib tosylate in advanced kidney cancer: past, present and future

The objective of this paper was to review the development of sorafenib tosylate in kidney cancer. The MedLine database, the Proceedings of the Annual American Society of Clinical Oncology meeting, as well as those of other key international meetings were extensively searched to identify relevant publications. Furthermore, the authors' direct experience with the drug was taken into account when commenting on the results retrieved. Sorafenib is a multikinase inhibitor that targets VEGF and PDGF receptors, other kinases, as well as the serine-threonine kinase Raf. Following early signs of activity from phase I and II studies, it has been shown to improve survival of pretreated advanced kidney cancer patients within a placebo-controlled, randomized, phase III trial, leading to its approval both in the United States and in Europe. Its activity has been subsequently confirmed in a real-world population by two expanded access programs performed globally, but not in a first-line setting; it also proved to be non-cross-resistant with two other molecularly targeted agents. Finally, its toxicity profile, which is acceptable and highly predictable, makes sorafenib appealing for combination treatments, especially with other molecularly targeted agents. Despite having been already demonstrated to be active in kidney cancer, the exact role of sorafenib in the first-line setting, in patients who have failed other molecularly targeted agents, and especially in combination with other agents, deserves further, prospective, studies.

Phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of oral alvespimycin (A; KOS-1022; 17-DMAG): Two different schedules in patients with advanced malignancies

14059 Background: A is ∼3–5 fold more potent compared to 17-AAG (the first Hsp90 inhibitor to enter clinical testing), based on in vitro cytotoxicity or the MTD in toxicology studies; it is water-soluble; and oral bioavailability in dogs is estimated at 40%. Toxicity in the dog included kidney, intestinal and liver findings. This study was conducted to determine the toxicity, MTD, recommended phase 2 dose (RP2D), PK and PD of A in pts with solid tumors. Methods: Escalating doses of A were given PO on 2 different schedules: every other day or daily for 4 out of 6 weeks. An initial IV dose was given to calculate absolute bioavailability. PK was evaluated after the IV dose, Day 1 and 21 of oral dosing. PBLs were collected to investigate changes in intracellular signaling proteins by immunoblot (Days 1 and 21 at 1, 3, 24 and 48 hours post-dose). Results: 28 pts were enrolled: 24 on the QOD schedule at doses of 5 (n=4), 10 (n=4), 20 (n=8), 30 (n=5) and 40 mg (n=3); 4 pts received 10mg on the QD schedule. 50% were male, median age/ECOG PS 55 and 0; median prior regimen 3. DLT has not yet been observed. Common drug-related toxicities (n=23): fatigue 43%, nausea 24%, anorexia 19%, proteinuria 19%, and peripheral edema 14%. Of these, fatigue and peripheral edema appear to be possibly dose-related. Drug-related Grade 3–4 toxicity (one patient each) included anemia, neutropenia, peripheral edema, hypokalemia, pain in extremity and hypoxia. For pts with full PK data (n=14), bioavailability equaled 51% and 49% on Day 1 and 21, and was not dose-dependent. Mean Day 21 AUCinf for the 5 to 30 mg/m2 levels equaled 91, 166, 542 and 1889 ng*h/mL. One pt with 3-fold increase in AUCinf comparing Day 1 and 21 dose had been started on dronabinol, a CYP2C9 inhibitor. One pt with fibrosarcoma (4 prior regimens) had necrotic changes in the tumor in the axilla with improved symptoms (active at 5+ months). Additional pts with SD include hemangioendothelioma (7 months), melanoma (6+ months), and renal cell (5 months). Induction in Hsp70 at the 30 mg dose level was seen pre-dose on Day 21 with maximal induction at 24 hours post-dose. Conclusions: Dose escalation continues on both schedules in order to define a RP2D. Toxicity is acceptable. Early signs of activity have been observed. [Table: see text]