Titration Design Research Articles

A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients with Relapsed or Refractory AML or CMML

A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients with Relapsed or Refractory AML or CMML

ACTR-55. OPTIMIZED TREAT-RESECT-TREAT STUDY DESIGN FOR CONVECTION-ENHANCED DELIVERY OF A FIRST-IN-CLASS BIOLOGIC IN THE TREATMENT OF GLIOBLASTOMA

Abstract INTRODUCTION Development of effective treatments for high-grade glioma (HGG) including glioblastoma is hampered by 1) the blood brain barrier, 2) an infiltrative growth pattern, 3) rapid development of adaptive therapeutic resistance, and 4) dose-limiting toxicity due to systemic exposure. Novel therapeutics and delivery techniques are warranted to overcome these obstacles and meaningfully improve patient outcomes. OS2966 is the first ever clinical-ready therapeutic candidate against the adhesion receptor subunit, CD29/β1 integrin. CD29 is highly overexpressed in glioblastoma and has been shown to drive tumor progression, invasion, and resistance to multiple modalities of therapy including immunotherapies. Here, we present a novel phase I trial design addressing all four obstacles plaguing effective treatment of HGG, while also enabling biomarker development. STUDY DESIGN This 2-part, ascending concentration, phase I clinical trial will enroll patients with recurrent/progressive HGG requiring a clinically-indicated resection. In part 1, patients will undergo stereotactic tumor biopsy followed by placement of a purpose-built catheter which is used for intratumoral convection-enhanced delivery (CED) of OS2966. Subsequently, patients undergo their clinically-indicated tumor resection followed by CED of OS2966 to the surrounding tumor-infiltrated brain. Matched, pre- and post-infusion tumor specimens will be utilized for biomarker development and validation of target engagement by receptor occupancy. Dose escalation will be achieved using a unique concentration-based accelerated titration design. DISCUSSION The present study design leverages multiple innovations including: 1) the latest CED technology, 2) two-part design including neoadjuvant intratumoral administration, 3) a first-in-class investigational therapeutic, and 4) concentration-based dosing. A U.S. Food and Drug Administration (FDA) Investigational New Drug application (IND) for the above protocol is now active.

439O - A first in human, phase I trial of NP137, a first-in-class antibody targeting netrin-1, in patients with advanced refractory solid tumors

BackgroundNetrin-1, a dependence receptor ligand, is overexpressed in many cancers and leads to resistance to cell death. In preclinical studies, targeting netrin-1 with the humanized anti-netrin-1 antibody NP137 inhibits tumor growth and metastasis. MethodsAdults with advanced, refractory solid tumors received NP137 IV Q2W, starting at 1mg/kg. Dose was escalated using a rapid titration design followed by a model-based design with 3-6 pts per cohort; Additional patients (pts) were enrolled in 4 biomarker cohorts, at dose levels that had been declared safe, starting at 6mg/kg, and underwent paired biopsies for pharmacodynamics (PD) purposes. ResultsNineteen pts were enrolled in 7 dose levels (1 to 20mg/kg). No DLTs were observed but 11 (58%) had infusion related reactions (IRR) of grade 1-2 severity, all at doses of 4mg/kg and above. Twenty-three pts were enrolled in the biomarker cohorts (up to 6 pts per cohort), and 18 (78%) experienced IRR. To date, 9 of 42 pts (21%) experienced at least one grade ≥ 3 drug related AE and 9 pts had at least one related SAEs (total of 14 SAEs including 10 IRRs and ischemic stroke, back pain, hyponatremia, pneumonia, n=1 each). Among 36 pts with at least one follow-up RECIST 1.1 assessment, 1pt with endometrial carcinoma had a confirmed PR (> 6 months to date, >50%, 14mg/kg) and 6 pts had SD at 3 months including one long-lasting SD over 1 year (cervical carcinoma, 6mg/kg) with a shrinkage > 30% in an irradiated lesion. To date, 3 pts are still on treatment (median duration: 43.0 days [7.0; 476.0]). Serum NP137 concentrations had biphasic disposition characteristic of both target and non-target-mediated clearances. PK data up to 5 consecutive cycles showed no evidence of NP137 accumulation. No ADAs were noted. RNAseq data on paired biopsies suggests that NP137 triggers a shift toward a more epithelial phenotype. Based on available data, 14mg/kg Q2W was selected as the RP2D. Recruitment in the extension phase is ongoing in gynecological tumors. ConclusionsNP137 was well-tolerated, with mild to moderate IRR as the most frequent treatment-related AEs and showed encouraging signs of clinical activity. Updated data will be presented at the meeting. Clinical trial identificationNCT02977195. Legal entity responsible for the studyCentre Léon Bérard. FundingNetris Pharma. DisclosureP. Cassier: Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Abbvie; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. Y. Courbebaisse: Full / Part-time employment: Netris Pharma. S. Depil: Advisory / Consultancy: Cellectis; Advisory / Consultancy: Netris Pharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: PDCLine Pharma; Advisory / Consultancy: Erytech; Advisory / Consultancy: Servier. J. Delord: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Roche/Genentech; Advisory / Consultancy: EMD Serono; Research grant / Funding (self): AstraZeneca. I.L. Ray-Coquard: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astr-Zeneca; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: PharmaMar; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GenMab. B. Ducarouge: Full / Part-time employment: Netris Pharma. P. Mehlen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netris Pharma. J. Blay: Non-remunerated activity/ies, uncompensated scientific advice: Netris Pharma. All other authors have declared no conflicts of interest.

700P - STAR-PAC: Phase I clinical trial repurposing all trans retinoic acid (ATRA) as stromal targeting agent in a novel drug combination for pancreatic cancer

BackgroundPreclinical data demonstrated that we can effectively target pancreatic stellate cells, with measurement of subsequent changes within the stroma, using all trans retinoic acid (ATRA). In a phase I trial we have repurposed ATRA as a stromal targeting agent in combination with gemcitabine and nab-paclitaxel (G-nP). MethodsPatients with locally advanced or metastatic pancreatic cancer, who had not received prior systemic therapy for their disease, were eligible. The primary objectives were to determine the maximum tolerated dose (MTD) and the optimal biological dose (OBD) of ATRA in combination with G-nP. Secondary objectives were to evaluate safety and tolerability, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of this combination. An accelerated titration design by the Bayesian Continuous Reassessment Method was used to determine the MTD. ResultsBetween Feb2016 and Feb2017, four UK centres enrolled 18 patients; between Jul2017 and Feb2018, two UK centres enrolled a further 10 patients who were treated at the MTD to ascertain the OBD. Most (24/28) patients had metastatic disease. The MTD and recommended phase 2 dose (RP2D) was gemcitabine (1000mg/m2 iv), nab-paclitaxel (125mg/m2 iv) both on days 1,8 and 15 of each 28day cycle and ATRA (45mg/m2 orally) in two divided doses from days 1 to 15 of each cycle. Dose limiting toxicities occurred in 2 patients (thrombocytopenia). The most common ≥ Grade 3 toxicities were asthenia (n=3), diarrhoea (n=2), neutropenia (n=2), peripheral neuropathy (n=2) and infection (n=2) in RP2D treated patients (n=19). Exploratory analysis showed median overall survival for RP2D treated patients receiving at least 2 cycles of chemotherapy or progressing within the first 2 cycles (n=15) was 11.66 months (95%CI 8.57-15.67), better compared to 8.5 (95%CI 7.9-9.5) months for G-nP in the MPACT trial (Von Hoff NEJM 2013). Pharmacodynamic data from DW-MRI, tissue and serum protein expression are suggestive of stromal modulation. ConclusionsAddition of ATRA as a stromal targeting agent to G-nP combination therapy is safe, tolerable. G-nP-ATRA will now be explored in a phase II randomised controlled trial for locally advanced pancreatic cancer. Legal entity responsible for the studyBarts Health NHS Trust. FundingMedical Research Council (MRC), Celgene. DisclosureAll authors have declared no conflicts of interest.

456P - First-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumours

456P - First-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumours

1377TiP - A phase Ia/Ib clinical study to evaluate the safety, pharmacokinetics (PK) and preliminary anti-tumour activity of FCN-159 in patients with advanced melanoma harboring NRAS-aberrant (Ia) and NRAS-mutation (Ib)

BackgroundGain of function mutations in NRAS occurs in 15-25% of patients with melanoma, leading to activation of Ras/Raf/MEK/ERK signaling pathway results in unconstrained cell growth and cell transformation. The MEK inhibitor targets this signaling pathway, inhibiting cell proliferation and inducing apoptosis. NRAS mutation status was identified as an independent poor prognostic factor in stage IV melanoma. It is also reported that the survival of patients with high copy number (>4) was significantly worse than that of NRAS patients with 2-4 copy number (P=0.002). No drug was approved to treat melanoma patients with NRAS mutation or amplification until now. FCN-159, an oral and potent MEK1/2 inhibitor, has more than 10 folds higher selectivity against activated MEK1 and MEK2 compared with trametinib, and has demonstrated significant antitumor growth inhibition in two patient-derived xenograft (PDX) models with NRAS mutation. This is the first in human study to evaluate the safety and anti-tumor activity of FCN-159 in patients. Trial designThis is a phase Ia/Ib, open label, dose-escalation study with expansion cohort that will evaluate the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of FCN-159 in up to 37 patients with locally advanced or metastatic melanoma harboring NRAS-aberrant including both NRAS amplification and mutation (Ia) and NRAS-mutation only (Ib). In this study, the dose escalation utilizes 3+3, accelerated titration design with starting dose of 0.2mg, QD, orally; the dose will be escalated until Maximum-Tolerated Dose (MTD) or the Recommended phase II dose (RP2D) being identified. The dose level will be considered to expand up to 6 patients if an objective response is observed, intending to collect more clinical data to support the RP2D determination. Once the MTD or RP2D is identified, an expansion cohort will be followed to further evaluate the safety and efficacy of FCN-159 in patients with NRAS-mutant melanoma. As of April 22, 2019, one patient has been dosed. Legal entity responsible for the studyShanghai Fosun Pharmaceutical Development Co, Ltd. FundingShanghai Fosun Pharmaceutical Development Co, Ltd. DisclosureAll authors have declared no conflicts of interest.

Titration Design: An Important Key in Drug Dose Determination

Drug titration is the process of adjusting the dose of a medicine for the maximum benefits without adverse effects. To determine the optimum dose range the clinical trials are carried out and it is divided into two types of study design. The parallel type study design and titration type study design. The titration studies provide the information about the cumulative effects of the drug. Titration designs are mainly used in dose determining especially in insulin, anticonvulsants, anti-depressants, and sedatives. In the analysis of titration design, the phase I, II, III clinical trials are carried out to determine the dose-response relationship, safety and efficacy of the drug.

Trial in progress abstract phase I trial of 5-aza-4’-thio-2’-deoxycytidine (Aza-TdC) in patients with advanced solid tumors.

TPS3148 Background: The nucleoside analog 5-aza-4’-thio-2’-deoxycytidine (Aza-TdC) inhibits DNA methyltransferase 1 (DNMT1), a methyltransferase involved in methylation-mediated silencing of tumor suppressor genes. Attenuation of DNA methylation via DNMT1 inhibitors results in reactivation of silenced tumor suppressor genes and can lead to tumor growth arrest and apoptosis. The DNMT1 inhibitors decitabine and 5-azacytdine are currently FDA-approved for use in myelodysplastic syndromes and are also used in patients with acute myeloid leukemia. Relative to these compounds, Aza-TdC exhibits enhanced stability and incorporation into DNA and has shown improved preclinical antitumor activity in both leukemia and solid tumor xenograft models. This study seeks to evaluate the safety and maximum tolerated dose (MTD) of oral Aza-TdC in patients with advanced solid tumors. Secondary study objectives include assessing objective response by RECIST 1.1, pharmacokinetic (PK) analysis, and examining re-expression of tumor suppressor genes inhibited by methylation in circulating tumor cells (CTCs). Methods: Patients are treated with Aza-TdC on days 1-5 and 8-12 of each 21-day cycle. The study follows Simon accelerated titration design 3, with 100% dose increments and 1 patient per dose level. Accelerated titration will continue until 1 patient experiences a dose-limiting toxicity (DLT) or 2 patients experience drug-related grade 2 toxicity at any dose level, after which, a 3 + 3 dose escalation design will be used. Blood samples are collected for PK and CTC analyses. An MTD expansion cohort is planned, in which tumor biopsies will be collected for further pharmacodynamic assessments. Patients included in this study must be ≥18 years old and have histologically documented solid tumors that have progressed on standard therapy and for which there is no other standard therapy available. Dose level 3 has been completed without any DLTs; enrollment to dose level 4 began in February 2019. Funded by NCI Contract No. HHSN261200800001E. Clinical trial information: NCT03366116.

A first-in-human phase I/II trial of SRA737 (a Chk1 Inhibitor) in subjects with advanced cancer.

3094 Background: SRA737 is a potent, highly selective and orally-bioavailable inhibitor of checkpoint kinase 1 (Chk1). SRA737-01 was designed to investigate the safety and tolerability of continuous, daily dosing with SRA737 and to evaluate preliminary efficacy in expansion cohorts of prospectively-selected genetically-defined subjects with advanced tumors. Methods: The escalation phase employed an accelerated titration design starting at 20 mg administered orally in 28-day cycles. Incremental 100% dose escalations in single-subject cohorts were followed by a rolling-6 design once SRA737-related ≥ Grade 2 toxicity was observed during Cycle 1. The expansion phase enrolled subjects prospectively selected by next-generation sequencing with: high grade serous ovarian, colorectal, metastatic castration-resistant prostate, non-small cell lung, and head and neck cancers. Results: In escalation, 18 subjects received SRA737 in 9 dose level cohorts, from 20 to 1300 mg QD; median treatment duration 62.5 days (range 1 to 226). Of these subjects, 3 experienced dose limiting toxicity (DLT; inability to receive 75% of the planned dose); 2 at 1300 mg QD due to gastrointestinal intolerability and 1 at 500 mg BID due to thrombocytopenia. The maximum tolerated dose (MTD) was established at 1000 mg QD or 500 mg BID. The Cmax and AUC0-24 at 1000 mg QD were 2391 ng/mL and 26795 ng∙h/mL respectively and the Cmin (411 ng/mL) exceeded that determined in preclinical models to be effective. Doses ≥ 300 mg QD also exceeded this level. Of 462 subjects prospectively screened for genetic alterations associated with Chk1 sensitivity, 93 were enrolled in expansion across all tumor types. Overall, the most commonly reported treatment-emergent adverse events were diarrhea (70%), nausea (64%), vomiting (51%), and fatigue (47%); the majority were of mild to moderate severity. Conclusions: In this first-in-human trial of SRA737 monotherapy, the MTD was 1000 mg/day and based on overall tolerability and PK, the recommended Phase 2 dose is 800 mg/day. The successful enrollment of prospectively-selected genetically-defined subjects will allow response data to be correlated with genomic profiles hypothesized to confer sensitivity to Chk1 inhibition. Clinical trial information: NCT02797964.

A phase ib trial to evaluate the safety and efficacy of quinacrine plus capecitabine in patients with refractory metastatic colorectal cancer.

e15020 Background: Acridines emerged from a cell-based screen for p53-pathway restoring compounds. Quinacrine, an acridine demonstrating p53 pathway restoration properties, displayed preclinical anti-tumor effects when used as monotherapy in colorectal cancer (CRC) cell culture and in vivo xenografts. Quinacrine suppresses survival pathways by inhibiting Mcl-1 expression, NFkB, STAT3, and angiogenesis. The combination of quinacrine plus 5-FU showed in-vivo preclinical efficacy against CRC with mutant KRAS, BRAF, or p53. Capecitabine, an oral 5-FU prodrug, is FDA-approved to treat metastatic (m)CRC. This phase I trial evaluated the safety and efficacy of quinacrine plus capecitabine in patients with refractory mCRC. Methods: Patients ≥18 years old with histologically confirmed mCRC refractory to standard therapy or with no standard therapy options available were eligible for the study. Using a modified 4B Simon’s accelerated titration design, patients were treated with a fixed dose of capecitabine 1000 mg/m2 twice daily (bid) for 14 days of a 21-day cycle, and escalating doses of quinacrine 100 mg daily, 100 mg bid, and 200 mg bid for 21 days. The primary endpoint was to identify the maximum tolerated dose (MTD) of quinacrine in combination with capecitabine and to determine their tolerability and safety. Results: Ten patients were enrolled, median age 60-years old (range: 56-79). Quinacrine 100 mg daily and 100 mg bid were well tolerated by the first two patients. Dose Limiting Toxicities (DLTs) were seen in 3 patients treated with quinacrine 200 mg bid and included hyperbilirubinemia, transaminitis, increased alkaline phosphatase, hypokalemia, diarrhea, vomiting, and dehydration. No grade 4 or 5 toxicities were seen. 5 additional patients tolerated treatment with quinacrine 100 mg bid and capecitabine without further DLTs making this the MTD. The median time on treatment was 63 days. Three patients came off study prior to their first response evaluation. In 7 patients evaluable for response, 4 had stable disease (57%), while 3 (43%) had disease progression. Median overall survival was 196.5 days. Conclusions: Capecitabine and quinacrine can be safely administered at the MTD of capecitabine 1000 mg/m2 PO bid D1-14 and quinacrine 100 mg PO bid D1-21 of a 21-day cycle for patients with mCRC. A phase II study is ongoing. Clinical trial information: NCT01844076.

FPT155-001: A phase Ia/Ib study of FPT155 (CD80-FC) in patients with advanced solid tumors.

TPS42 Background: Despite recent advances in immunotherapy, many patients with advanced solid tumors are refractory to available therapies or eventually relapse. Novel immune therapies are needed with differentiated mechanisms of action that result in improved response rates and durability across a broad range of tumors. FPT155 is a first-in-class therapeutic being developed to meet this need. FPT155 is a recombinant fusion protein composed of the extracellular domain of human CD80 fused with the Fc domain of human immunoglobulin G1. It is designed to act as a potent stimulator of anti-tumor immunity through CD28 and thereby co-stimulate T cell responses only in the presence of antigenic T cell receptor (TCR) signaling. FPT155 alone does not induce spontaneous cytokine release by primary human immune cells, in contrast to a CD28 superagonist antibody that exerts TCR stimulus-independent activity. FPT155 also blocks CTLA-4 from competing for endogenous CD80, allowing CD28 signaling to prevail in T cell activation. A murine surrogate of FPT155 is a potent inhibitor of tumor growth that induces complete tumor regression in multiple tumor models, including models that are insensitive to anti-PD1 or anti-CTLA4. Methods: The FPT155-001 study is a Phase 1a/1b open-label, multicenter, dose escalation and expansion study to evaluate the safety and tolerability of FPT155 monotherapy. Phase 1a dose escalation includes an accelerated titration design followed by a standard 3+3 design until the recommended dose for Phase 1b is determined by evaluation of all available safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. Eligible patients with advanced solid tumors who are refractory to all standard therapy for their malignancy will be enrolled in Phase 1a. Phase 1b dose expansion will enroll patients with select tumor types. The primary endpoint is safety in both phases. Key secondary endpoints in Phase 1a include characterization of the FPT155 PK profile and immunogenicity. Key secondary endpoints in Phase 1b include objective response rate, duration of response, progression free survival, and disease control rate. The FPT155-001 trial opened for enrollment in October 2018 and is in progress. Clinical trial information: Submitted - awaiting registration number.

A phase I study evaluating COM701 in patients with advanced solid tumors.

TPS40 Background: Novel checkpoint therapies are needed for the treatment of patients who relapse/refractory to treatment with checkpoint inhibitors. COM701 is a novel first-in-class humanized IgG4 monoclonal antibody that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG) blocking its interaction with it's ligand, PVRL2. We have demonstrated in preclinical experiments that inhibition of PVRIG leads to activation of T cells in the tumor microenvironment generating an anti-tumor immune response leading to tumor growth inhibition. We hypothesize that COM701 will be safe and tolerable and demonstrate antitumor activity in pts with R/R solid tumors. Methods: NCT03667716 is an ongoing open-label first-in-human phase 1 study in pts with R/R solid tumors. The initial part of this study will evaluate the safety and tolerability of escalating doses of COM701 monotherapy IV Q3 weekly. Key Inclusion Criteria: Age ≥18 yrs, histologically or cytologically confirmed, locally advanced or metastatic solid malignancy and has exhausted all the available standard therapy or is not a candidate for the available standard therapy, ECOG performance status 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137. Key Exclusion Criteria: Active autoimmune disease requiring systemic therapy in the last 2 years prior to the first dose of COM701, symptomatic interstitial lung disease or inflammatory pneumonitis, untreated or symptomatic central nervous system metastases. Primary outcome measures are the incidence of adverse events and dose-limiting toxicities (21-day DLT window), pharmacokinetics of COM701 and to identify the maximum tolerated dose and/or the recommended dose for expansion. Secondary outcome measures are to characterize the immunogenicity and preliminary antitumor activity of COM701. Study Design: Accelerated titration design consisting of single subject cohorts has been implemented for the initial cohorts. Statistical Considerations: Adverse events graded as per CTCAE v4.03, responses as per RECIST v1.1. The analyses of all study objectives will be descriptive and hypothesis generating. As of the date of this submission a third single subject dose cohort has been filled.

A Phase 1 Study Investigating AFM11 in Patients with Relapsed/Refractory B Cell Precursor Acute Lymphoblastic Leukemia: Preliminary Results

BackgroundAFM11 is a bispecific, tetravalent T cell-engaging antibody construct binding to CD19 on B cell origin malignant cells such as B-precursor acute lymphoblastic leukemia (B-ALL) and to CD3 on T cells. By engaging CD3-positive T cells, AFM11 elicits T cell-mediated killing of CD19-positive (CD19+) leukemia and lymphoma cells. In vivo anti-tumor activity of AFM11 was investigated in a Raji tumor xenograft model in non-obese diabetic/severe combined immunodeficiency (NOD/scid) mice reconstituted with human peripheral blood mononuclear cells (PBMC). Tumor growth in all AFM11-treated animal groups was significantly reduced. In the highest dose group, all animals achieved complete tumor remission. (Reusch et al., 2015). An ongoing Phase 1 study assesses safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AFM11 in patients with relapsed/refractory (R/R) CD19+ B-ALL.MethodsPatients (pts) with relapsed or refractory CD19+ B-ALL are being enrolled into escalating cohorts of 1-6 pts. The primary objective of the study is to determine the maximum tolerated dose (MTD) of AFM11 administered as a 2-week continuous intravenous (CIV) infusion. AFM11 is administered over the first 2 weeks (wks) of each 4 wk cycle for up to 3 cycles. Pts with rapidly progressing disease receive pre-treatment with 200 mg cyclophosphamide and 10 mg/m2 dexamethasone over 3-5 days before initiating AFM11. A lower starting dose is employed during the first wk of cycle 1 and escalated to a target dose during the second wk of cycle 1 and all subsequent cycles. An accelerated titration design is used until toxicity is observed, followed by a classical 3+3 design. PD activity is assessed by flow cytometry of peripheral blood lymphocytes and serum cytokine measurements. Tumor response is evaluated by local bone marrow and peripheral blood laboratory results between days 15 and 18 of each cycle.ResultsAs of June 29, 2018, fourteen pts (8 female/6 male) have been treated in 5 cohorts. The median age is 41.5 years (range 19-67) and the median number of prior therapies is 5 (range 1-12). AFM11 was well-tolerated with no dose-limiting toxicities (DLTs) observed in the first 5 cohorts. The study switched to 3+3 design in cohort 3 due to the occurrence of grade 2 AFM11-related events in cohort 2. Enrollment into cohort 6 is ongoing and the MTD has not yet been reached.The most frequent (≥2 pts) AFM11-related adverse events were pyrexia (29%), myalgia (14%), and tremor (14%). Most of the events were Common Terminology Criteria for Adverse Events (CTCAE) v4.03 grade 1-2, with one grade 3 and no grade 4 events observed. Transient and reversible neurological events occurred in 3 of 14 (21%) pts: grade 1 paresthesia (n=1), grade 1/grade 2 tremor (n=1 each), grade 2 lethargy (n=1); and grade 3 altered state of consciousness (n=1). The grade 3 event occurred during the third cycle of treatment and was managed with treatment interruption and steroids and resolved within 48 hours. The pt then completed the third cycle at a reduced AFM11 dose without incident.Peripheral B cell reductions were observed in multiple pts in cohorts 4 and 5 and notable cytokine release was detected in two pts. Two pts achieved complete remission with complete hematological recovery (CR): one pt in cohort 4 achieved CR after the first cycle and progressed 2 wks later; one pt in cohort 5 achieved CR after the first cycle which was sustained after the second and third cycles and was assessed as minimal residual disease (MRD) negative after cycle 3. As a result, this pt became eligible to receive stem cell transplantation upon study completion. Both CR pts had peripheral B-cell aplasia after the first few days of treatment. Updated data will be presented.ConclusionsThe CD19/CD3-targeting tetravalent bispecific T cell engager AFM11 was well-tolerated in pts with R/R B-ALL across the first 5 cohorts of an ongoing Phase 1 study, and the MTD has not been reached. Pyrexia was the most frequently observed related adverse event. Transient neurological events were observed and were consistent with those associated with other CD19-targeted therapies. Peripheral B cell reductions and complete remissions observed in pts treated in the higher dose cohorts suggest that AFM11 is active in pts with R/R B-ALL and that the study is nearing determination of the therapeutic dose and schedule. DisclosuresSalogub:Affimed: Research Funding. Mayer:Novartis: Research Funding; Roche: Research Funding; Eisai: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Folber:Affimed: Research Funding. Grosicki:Affimed: Research Funding. Skotnicki:Affimed: Research Funding. Prochwicz:Affimed: Research Funding. Myasnikov:Affimed: Research Funding. Gural:Affimed: Research Funding. Schoenborn-Kellenberger:Affimed: Consultancy. Brindley:Affimed: Consultancy. Knackmuss:Affimed: Employment. Schwarz:Affimed: Employment. Schmich:Affimed: Employment. Choe-Juliak:Affimed: Employment. Strassz:Affimed: Employment. Alland:Affimed: Employment. Doubek:AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Affimed: Research Funding; Novartis: Consultancy.

Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial)

BackgroundTriple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study TNBC cells were treated with the first-generation proteasome inhibitor bortezomib in combination with cisplatin and synergistic efficacy was demonstrated. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity and good tolerability (Mol Cancer 11:26 2012, J Thorac Oncol 4:87–92 2009, J Thorac Oncol 7:1032–1040, 2012). Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC.MethodsPatients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease according to RECIST criteria 1.1 are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study utilizes an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), the efficacy and safety of the combination will be further evaluated (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include progression-free survival, safety, and quality of life. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within 2 years.DiscussionBased on preclinical and clinical findings an ixazomib and carboplatin combination is thought to be effective in metastatic TNBC patients. The MBC-10 trial is accompanied by a broad biomarker program investigating predictive biomarkers for treatment response and potential resistance mechanisms to the investigational drug combination.Trial registrationEudraCT Number: 2016–001421-13 received on March 31, 2016, ClinicalTrials.gov Identifier: NCT02993094 first posted on December 15, 2016. This trial was registered prospectively.

Abstract CT019: ASN003, a novel highly selective BRAF and PI3K dual inhibitor: Phase I PK/PD results in patients with advanced solid tumors

Abstract Background RAS-RAF-MEK and PI3K-AKT-mTOR are two major pathways involved in tumor cell signaling and growth. Components of these pathways are frequently mutated in a broad range of tumors. ASN003 is a highly selective and potent (low nM IC50) inhibitor of BRAF and PI3K-α and -δ. ASN003 shows strong antitumor activity in tumor models harboring BRAF and PIK3CA mutations, and also in patient-derived xenograft (PDX) models that are resistant to selective BRAF and MEK inhibitors. Patients and Methods: Oral once-daily ASN003 is being evaluated for safety/tolerability and preliminary efficacy in eligible patients with advanced solid tumors using an accelerated dose titration design (Part A) and enrolling cohorts of patients diagnosed with melanoma, CRC, NSCLC and other solid tumors with a BRAF, PIK3CA mutations at MTD (Part B). Pharmacokinetic (PK) profile and the pharmacodynamic (PD) effects of ASN003 on tumor tissue biomarkers such as pERK and pS6 are being investigated in both parts of the study. Results: Patient accrual in Part A is ongoing. As of January 2018, fifteen eligible patients were enrolled in dose levels ranging from 10 - 400 mg QD and 400 mg BID. ASN003 has been well tolerated. Treatment-related adverse events (TRAEs) were mostly mild (G1) to moderate (G2). TRAEs include, rash (G3), hypersensitivity (G3) (n=1), diarrhea (G2) (n=1), hyperglycemia (G2) (n=1), rash maculo-papular (G2) (n=1), vomiting (G1) (n=3), nausea (G1) (n=2), hyperglycemia (G1) (n=2), and dry mouth/lips/skin, transient blurred vision, rash acneiform, ALT increase, cognitive disturbance and hyperkalemia. The PK profile showed dose-dependent increase in systemic exposure at steady state (Cmax up to 5,990 ng/mL, AUC0-T up to 110,000 ng.h/mL) and a half-life of 14-25 hours in general. Early evidence of biomarker changes in repeat biopsies, and clinical disease control have been observed. Conclusions: ASN003 is a novel small molecule, with uniquely selective and potent inhibition of BRAF, PI3K-α and -δ kinases. To date, ASN003 was well tolerated at doses up to 400 mg QD/BID and achieved good systemic exposure. Updated and detailed clinical safety/efficacy and PK/PD results will be presented. Citation Format: Drew Rasco, Nehal Lakhani, Ryan Sullivan, Monica Mita, Jaimini Shah, Helen Usansky, Sanjeeva Reddy, Niranjan S. Rao, Sarper Toker, Louis Denis, Keith Flaherty, Anthony Tolcher. ASN003, a novel highly selective BRAF and PI3K dual inhibitor: Phase I PK/PD results in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT019.

Abstract CT160: Ixazomib in combination with carboplatin in pretreated women with advanced triple negative breast cancer, an ongoing phase I/II trial (AGMT MBC-10 trial)

Abstract Background: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Recently, the PARP inhibitor olaparib was approved as first targeted treatment beyond antiVEGF therapy for the BRCA1/2 mutated subgroup of TNBC. However, cytotoxic agents still remain the mainstay of treatment for this breast cancer subtype. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated as treatment of multiple myeloma. In a preclinical cell line model for TNBC the first-generation proteasome inhibitor bortezomib showed synergistic efficacy with cisplatin. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity (47% and 38% response rate, respectively) and good tolerability. In solid tumors cytotoxic effect of proteasome inhibitors is thought to be mediated through different mechanisms: (1) Inhibition of the Fanconi Anemia and BRCA1 DNA repair mechanism (2) Inhibition of p53 degradation (3) Inhibition of NF-kappa B signaling cascade. Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the oral second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC. Trial Design: Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study uses an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), accrual continues to evaluate the efficacy and safety of the combination (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include safety profile, progression-free survival and quality of life. The MBC-10 trial is accompanied by a broad biomarker program investigating predictive biomarkers for treatment response and potential resistance mechanisms to the investigational drug combination. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within two years. ClinicalTrials.gov Identifier: NCT02993094 Citation Format: Gabriel Rinnerthaler, Simon P. Gampenrieder, Andreas Petzer, Renate Pusch, Daniela Voskova, Dieter Rossmann, Marija Balic, Daniel Egle, Holger Rumpold, Christian F. Singer, Thomas Melchardt, Hanno Ulmer, Brigitte Mlineritsch, Richard Greil. Ixazomib in combination with carboplatin in pretreated women with advanced triple negative breast cancer, an ongoing phase I/II trial (AGMT MBC-10 trial) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT160.

Responses of Daphnia magna to chronic exposure of cadmium and nickel mixtures

The present study assessed the chronic toxicity of cadmium (Cd) and nickel (Ni) mixtures to Daphnia magna. Using a titration design, Ni concentrations of 20, 40, 80, 100, 120, 140, and 160 μg/L were tested alone and simultaneously titrated in increments against a constant concentration of 1.5 μg/L Cd. The results demonstrated that Cd at 1.5 μg/L was highly toxic to D. magna, and Ni alone concentrations ≥80 μg/L were toxic to D. magna survival, reproduction, and growth. No Ni alone concentration was found to induce a toxic effect on undeveloped embryos and the time to first brood. Only the Ni alone treatment containing 200 μg/L affected the reproductive rates of D. magna. For CdNi mixtures, Ni concentrations of 20, 40, and 80 μg/L were found to strongly protect D. magna from Cd toxicity at the survival and growth endpoints, resulting in less-than-additive effects, but not on the reproductive endpoint. At higher concentrations, Ni exceeded the necessary concentration needed to protect D. magna, and appeared to contribute to the toxicity. Overall, the results of metal uptake support the competitive binding mechanism at the biotic ligand and explain the less-than-additive effects observed in the CdNi mixtures concentration. The embryonic effects of CdNi mixtures are not explained by the competitive binding mechanism at the biotic ligand. More research is needed to determine the mechanisms that produce embryonic impairment when cellular metals interact. Overall, the results of the present study are relevant for the development of improved environmental quality guidelines for metal mixtures.

Abstract OT3-07-01: Ixazomib in combination with carboplatin in pretreated women with advanced triple negative breast cancer, an ongoing phase I/II trial (AGMT MBC-10 trial)

Abstract Background:Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Recently, the PARP inhibitor olaparib was approved as first targeted treatment beyond antiVEGF therapy for the BRCA1/2 mutated subgroup of TNBC. However, cytotoxic agents still remain the mainstay of treatment for this breast cancer subtype. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated as treatment of multiple myeloma. In a preclinical cell line model for TNBC the first-generation proteasome inhibitor bortezomib showed synergistic efficacy with cisplatin. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity (47% and 38% response rate, respectively) and good tolerability. In solid tumors cytotoxic effect of proteasome inhibitors is thought to be mediated through different mechanisms: (1) Inhibition of the Fanconi Anemia and BRCA1 DNA repair mechanism (2) Inhibition of p53 degradation (3) Inhibition of NF-kappa B signaling cascade. Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the oral second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC. Trial Design: Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease are eligible for this study.Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study uses an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), accrual continues to evaluate the efficacy and safety of the combination (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include safety profile, progression-free survival and quality of life. The MBC-10 trial is accompanied by a broad biomarker program investigating predictive biomarkers for treatment response and potential resistance mechanisms to the investigational drug combination. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within two years. ClinicalTrials.gov Identifier: NCT02993094 Citation Format: Rinnerthaler G, Gampenrieder SP, Petzer A, Burgstaller S, Voskova D, Rossmann D, Balic M, Egle D, Rumpold H, Singer CF, Petru E, Melchardt T, Ulmer H, Mlineritsch B, Greil R. Ixazomib in combination with carboplatin in pretreated women with advanced triple negative breast cancer, an ongoing phase I/II trial (AGMT MBC-10 trial) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-07-01.

Abstract OT2-07-11: Ixazomib in combination with carboplatin in pretreated women with advanced triple negative breast cancer, a phase I/II trial (AGMT MBC-10 trial)

Abstract Background: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with a poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy is approved for TNBC so far and cytotoxic agents are the mainstay for the treatment of advanced tumor stages. Ixazomib is a selective, and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study triple-negative breast cancer cells were treated with bortezomib, a first generation proteaseome inhibitor, alone and in combination with cisplatin, which had a synergistic effect. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity and good tolerability. Based on this rational, the MBC-10 trial will evaluate the toxicity profile and efficacy of ixazomib in combination with carboplatin in patients with advanced TNBC. Trial Design: Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study uses an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), accrual continues to evaluate the efficacy and safety of the combination (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include safety profile, progression-free survival and quality of life. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within two years. ClinicalTrials.gov Identifier: NCT02993094 Citation Format: Rinnerthaler G, Gampenrieder SP, Petzer A, Pusch R, Fridrik M, Rossmann D, Balic M, Egle D, Rumpold H, Singer C, Bartsch R, Melchardt T, Ulmer H, Mlineritsch B, Greil R. Ixazomib in combination with carboplatin in pretreated women with advanced triple negative breast cancer, a phase I/II trial (AGMT MBC-10 trial) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-11.

Abstract B147: A phase 1 PK/PD study of ASN003, a novel, highly selective BRAF and PI3K dual inhibitor, in patients with advanced solid tumors

Abstract Background: RAS-RAF-MEK and PI3K-AKT-mTOR are two major pathways involved in tumor cell signaling and growth. Components of these pathways are frequently mutated in a broad range of tumors. ASN003 is a highly selective and potent (low nM IC50) inhibitor of BRAF and PI3K-α and -δ (low affinity for PI3K-β). ASN003 shows strong antitumor activity in tumor models harboring BRAF and PIK3CA or PTEN mutations, and also in patient-derived xenograft (PDX) models that are resistant to selective BRAF and MEK inhibitors. Patients and Methods: Oral once-daily ASN003 is being evaluated for safety/tolerability and preliminary efficacy in eligible patients with advanced solid tumors using an accelerated dose titration design (Part A) and enrolling cohorts of patients diagnosed with melanoma, CRC, NSCLC, and other solid tumors with a BRAF, PIK3CA, or PTEN mutation at MTD (Part B). Pharmacokinetic (PK) profile and the pharmacodynamic (PD) effects of ASN003 on tumor tissue biomarkers such as pERK and pS6 are investigated in both parts of the study. Results: Patient accrual in Part A is ongoing. As of June 2017, nine eligible patients are enrolled in dose levels ranging from 10 - 240 mg QD. ASN003 has been well tolerated. Treatment-related adverse events (TRAEs) were mild (G1) to moderate (G2). TRAEs include diarrhea (G2) (n=1), nausea/vomiting (G1), blurred vision (G1), and dry mouth/lips/skin (G1). Transient G1 elevation of glucose and insulin c-peptide levels has been noted in 1 pt. No G3/4 or serious TRAEs have been observed to date. The PK profile showed dose-dependent, systemic exposure with Cmax ranging from 74 to 1055 ng/mL, AUCT from 912 to 20100 ng.h/mL. Conclusions: ASN003 is a novel small molecule, with uniquely selective and potent inhibition of BRAF, PI3K-α and -δ kinases. To date, ASN003 was well tolerated at doses up to 240 mg QD and achieved good systemic exposure. Updated and detailed clinical safety/efficacy and PK/PD results will be presented. Citation Format: Drew Rasco, Nehal Lakhani, Ryan Sullivan, Monica Mita, Jaimini Shah, Helena Usansky, Sanjeeva Reddy, Niranjan Rao, Louis J. Denis, Anthony Tolcher, Keith Flaherty. A phase 1 PK/PD study of ASN003, a novel, highly selective BRAF and PI3K dual inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B147.