scholarly journals ACTR-15. PHASE 1 TRIAL OF A KETOGENIC DIET IN PATIENTS RECEIVING STANDARD-OF-CARE TREATMENT FOR RECENTLY DIAGNOSED GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi15-vi15
Author(s):  
Gillian Gresham ◽  
Lauren Amaral ◽  
Laura Lockshon ◽  
Dana Levin ◽  
Jeremy Rudnick ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
Medical Center ◽  
Phase 1 ◽  
Standard Of Care ◽  
Preliminary Evidence ◽  
Feasibility Trial ◽  
Open Label ◽  
Immune Biomarkers ◽  
Standard Of Care Treatment ◽  
High Doses

Abstract BACKGROUND There is abundant interest in the potential therapeutic and supportive role of a ketogenic diet (KD) in patients with glioblastoma (GBM). The KD is a high fat/low carbohydrate metabolic therapy that modulates several of the bioenergetic and biosynthetic pathways that are dysregulated in GBM. To date, studies of the KD in cancer patients have been limited in scope. This study will provide preliminary evidence on the safety and feasibility of a 16-week ketogenic diet in patients with GBM. METHODS This is an open-label single-arm feasibility trial being conducted at Cedars-Sinai Medical Center. We will recruit 20 recently diagnosed GBM patients who are receiving standard-of-care (SOC) treatment. Patients may enroll within 3 months of diagnosis, thus allowing patients who have already begun SOC chemoradiation the opportunity to participate. Excluded are patients with a KPS < 70, BMI < 22, or on high doses of steroids. Consenting patients will maintain a 16-week ketogenic diet (KD) supervised and monitored by study dietitians (RD). The primary outcome of safety will be assessed by monitoring weight, BMI, and adverse events. Secondary outcomes are: 1) Adherence to the KD, as assessed by BID blood glucose and ketone levels; 2) Time to progression and overall survival from date of KD initiation 3) Mean change in overall QOL, as measured using the QLQ30 and QLQ-BN20 questionnaires; and 4) Mean change in cognitive scores at 16 weeks from baseline. Exploratory outcomes include metabolic, inflammatory, and immune biomarkers; gut microbiota analysis; large oncosome analysis; and daily activity assessed with a wearable activity monitor. This novel trial incorporates multiple digital devices and mobile applications into the study design. Accrual is ongoing with 10 patients currently enrolled (NCT03451799).

QOLP-04. THE KETOGENIC DIET PLUS STANDARD CARE FOR RECENTLY DIAGNOSED GLIOBLASTOMA: A PHASE 1 SAFETY AND FEASIBILITY TRIAL

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi183-vi183
Author(s):  
Jethro Hu ◽  
L J Amaral ◽  
Gillian Gresham ◽  
Thomas Nelson ◽  
Amelia Welborn ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Primary Objective ◽  
Feasibility Trial ◽  
Phase 2 Trial ◽  
Related Quality ◽  
Health Related ◽  
Grade 3

Abstract INTRODUCTION There is abundant interest in the potential therapeutic and supportive role of a ketogenic diet (KD) for glioblastoma patients. We conducted a single-arm phase 1 trial to assess the safety and feasibility of KD plus standard-of-care (SOC) in glioblastoma patients (NCT03451799). METHODS Adults within 3 months of diagnosis participated in a 16-week intervention of a classic 3:1 KD (grams fat : grams carbohydrate + protein) with dietitian support. Blood glucose and ketone levels were assessed twice daily (Keto-Mojo), with remote monitoring of daily weight and activity (Fitbit). The primary objective was to assess safety (weight stability, CTCAE) and feasibility (maintaining ketosis &gt; 0.3mM for &gt; 50% of study period). Secondary objectives included assessments of progression-free survival (PFS), overall survival (OS), health-related quality of life (HRQOL), and cognition (MoCA). RESULTS From 04/2018-02/2021, 14 patients were evaluable: female:male, 8:6, median age 55 years, KPS 80, BMI 24.5. MGMT promoter methylation: 6 present, 7 absent, 1 indeterminate. Adherence to KD was high, with all patients maintaining ketosis ( &gt; 0.3mM) &gt; 50% and 11 patients maintaining ketosis &gt; 85% of study days. Adverse events (&gt; Grade 2) potentially attributable to KD: appetite loss (Grade 2: 2); fatigue (Grade 2: 5); flu-like symptoms (Grade 2: 1); constipation (Grade 2: 5, Grade 3: 1). No patients were removed from study for safety reasons. HRQOL was stable, with improvements in role function (not statistically significant). MoCA score improved in 10/14 patients. Median PFS and OS from KD initiation were 11.7 and 29.1 months, respectively. CONCLUSION Our findings suggest that a supervised KD plus SOC is safe and feasible in glioblastoma patients. KD was well-tolerated with encouraging trends in HRQOL and cognition. PFS and OS in this small trial compare favorably to historical control. A multicenter phase 2 trial powered to assess efficacy is planned.

ARC-9: Phase Ib/II study to evaluate etrumadenant (AB928)-based treatment combinations in patients with metastatic colorectal cancer (mCRC).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS150-TPS150
Author(s):  
Michael Cecchini ◽  
Kartik Krishnan ◽  
Nick Giafis ◽  
Jennifer Scott ◽  
Cheng Seok Quah ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Phase 1 ◽  
Clinical Stage ◽  
Atp Release ◽  
Standard Of Care ◽  
Stopping Rules ◽  
Clinical Activity ◽  
Open Label ◽  
Curative Intent ◽  
Platinum Based Chemotherapy

TPS150 Background: ATP release from dying cancer cells in response to platinum-based chemotherapy increases extracellular immunosuppressive adenosine, which binds and activates the A2a and A2b receptors on immune cells. Adenosine-mediated signaling impairs activation, proliferation, and cytotoxic activity of effector T cells, resulting in inhibition of antitumor activity. Concomitant adenosine receptor blockade may therefore enhance the therapeutic efficacy of chemo/immunotherapy regimens. Etrumadenant (AB928), the first clinical-stage, small-molecule, dual adenosine receptor antagonist, is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as monotherapy or combined with chemo/immunotherapy. Recently, results were reported for the ARC-3 phase 1/1b study of etrumadenant + modified 5-fluorouracil + oxaliplatin (mFOLFOX-6) in patients (pts) with mCRC. In this study, etrumadenant + mFOLFOX-6 was well tolerated without significant additive toxicity. Disease control was observed in patients with RAS/BRAF mutated mCRC, as well as 3L+ disease previously treated with FOLFOX and/or FOLFIRI (PR and/or SD >4 mo). Due to deep responses in 1L-3L+ pts, 6 pts had the opportunity to pursue surgery and radiotherapy with curative intent. The encouraging results from ARC-3 warrant further evaluation of etrumadenant-based combination therapy for mCRC. Methods: ARC-9 is a phase 1b/2, multicohort, open-label, randomized platform study designed to evaluate safety and clinical activity of etrumadenant (150 mg orally once daily [QD]) in combination with standard-of-care (SOC) regimens or novel therapeutics in pts with mCRC (Table). Cohort eligibility is based on prior anticancer treatment history. Pts enrolled in Cohorts A and B will be randomized (2:1) into the experimental vs SOC arms. Cohort C consists of a single arm to allow inclusion of novel agents as they become available with built in early stopping rules for futility. Pts who progress on the SOC arm of Cohort A can enroll in Cohort B; pts who progress on the SOC arm of Cohort B can crossover to the experimental arm. Primary endpoints across cohorts are shown in Table. Safety monitoring will occur throughout the trial, disease assessments will occur every 8 weeks, and correlative study pre- and on-treatment biopsies will be performed. [Table: see text]

Phase 1 Open-Label, Multicenter Study of First-in-Class RORγ Agonist LYC-55716 (Cintirorgon): Safety, Tolerability, and Preliminary Evidence of Antitumor Activity

2019 ◽  
Vol 25 (12) ◽  
pp. 3508-3516 ◽  
Author(s):  
Devalingam Mahalingam ◽  
Judy S. Wang ◽  
Erika P. Hamilton ◽  
John Sarantopoulos ◽  
John Nemunaitis ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Multicenter Study ◽  
Phase 1 ◽  
Preliminary Evidence ◽  
Open Label

Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1540-1540 ◽  
Author(s):  
Sheeba K. Thomas ◽  
Wael A. Harb ◽  
Joseph Thaddeus Beck ◽  
Gabrail Nashat ◽  
M. Lia Palomba ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Open Label ◽  
Label Dose ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

Abstract Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation. Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006). Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented. Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. Disclosures Thomas: Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.

BMS-986205, an indoleamine 2, 3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (nivo): Updated safety across all tumor cohorts and efficacy in advanced bladder cancer (advBC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 358-358 ◽  
Author(s):  
Jason J. Luke ◽  
Josep Tabernero ◽  
Anthony Joshua ◽  
Jayesh Desai ◽  
Andrea I. Varga ◽  
...  
Keyword(s):  
Phase 1 ◽  
Preliminary Evidence ◽  
Stevens Johnson Syndrome ◽  
Tumor Escape ◽  
Open Label ◽  
Indoleamine 2 ◽  
Johnson Syndrome ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Favorable Safety

358 Background: Nivo (anti–PD-1) has shown durable responses and manageable safety (ORR, 19.6%; grade 3‒4 treatment-related AEs [TRAEs], 18%) in advBC (Sharma et al. Lancet Oncol 2017), but prolonging survival in more pts requires additional approaches to overcome tumor evasion mechanisms. IDO1 allows tumor escape through kynurenine (KYN) production, which stimulates regulatory T cells and suppresses effector T-cell proliferation. Anti─PD-1 can upregulate IDO1, supporting the rationale for combining nivo with an IDO1i. BMS-986205 is a selective, potent, once-daily (QD) oral IDO1i that works early in the IDO1 pathway to reduce KYN production. BMS-986205 + nivo showed favorable safety and efficacy in heavily pretreated pts with select solid tumors (Luke et al. SITC 2017; NCT02658890). Updated safety across all tumor cohorts and efficacy in the immuno-oncology (I-O)–naive advBC cohort are reported. Methods: Dose-escalation methods in this phase 1/2a, open-label study were previously described; during expansion, pts received BMS-986205 100 or 200 mg QD + nivo 240 mg IV Q2W or 480 mg IV Q4W. Objectives included safety and ORR by RECIST v1.1 (includes unconfirmed responses). Results: As of Mar 2018, 516 pts received BMS-986205 + nivo; 45% had ≥2 prior regimens. TRAEs occurred in 57% of pts (grade 3‒4, 12%), the most common being fatigue (15%) and nausea (12%); 19 pts (4%) discontinued due to TRAEs, and 3 pts ( < 1%) died due to a TRAE (myocarditis, Stevens-Johnson syndrome, and hepatic failure). In all treated pts and within the advBC cohort (n = 30), the frequency and severity of TRAEs and rate of discontinuation due to TRAEs was lower with the 100- vs 200-mg BMS-986205 dose. Among the 27 pts with I-O–naive advBC, with a median duration of follow-up of 24 wk, ORR was 37% (3 CRs, 7 PRs), and the DCR was 56%; ORR in pts with tumor PD-L1 ≥1% (Dako PD-L1 IHC 28-8 pharmDx assay; n = 14) vs < 1% (n = 10) was 50% vs 30%. Conclusions: BMS-986205 + nivo was well tolerated in heavily pretreated pts, and tolerability was improved with the 100-mg BMS-986205 dose. Preliminary evidence of efficacy was observed in advBC, supporting further evaluation of BMS-986205 + nivo. Clinical trial information: NCT02658890.

The AIM-HN and SEQ-HN study: A pivotal study evaluating the efficacy of tipifarnib in patients with head and neck squamous cell carcinoma (HNSCC) with hras mutations (AIM-HN) and the impact of hras mutations on response to first line systemic therapies for HNSCC (SEQ-HN).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS6593-TPS6593
Author(s):  
Robert I. Haddad ◽  
Kevin Joseph Harrington ◽  
Lisa F. Licitra ◽  
Amanda Psyrri ◽  
Nabil F. Saba ◽  
...  
Keyword(s):  
Final Analysis ◽  
Standard Of Care ◽  
Patient Characteristics ◽  
Unknown Primary ◽  
Missense Mutations ◽  
First Line ◽  
Open Label ◽  
Significance Level ◽  
Standard Of Care Treatment ◽  
The Impact

TPS6593 Background: HRAS mutations define a unique molecular subset of ~ 5% of HNSCC. Evidence suggests that these tumors respond poorly to standard systemic therapy but the impact of HRAS missense mutations on clinical outcomes has not been formally characterized. Tipifarnib is a potent and selective inhibitor of farnesyltransferase, a critical enzyme for HRAS activity. Phase 2 Proof of concept for tipifarnib in HRAS mutant HNSCC was recently achieved in study KO-TIP-001 (NCT02383927, Ho et. al. ESMO 2018). Methods: The AIM-HN and SEQ-HN Study (KO-TIP-007, NCT03719690) is an ongoing international, multicenter, open-label, 2 cohort (AIM-HN and SEQ-HN), pivotal trial designed to determine the Overall Response Rate (ORR) of tipifarnib in patients (pts) with HRAS mutant HNSCC (AIM-HN). SEQ-HN will retrospectively investigate how the ORR to first line treatment compares between the accrued HRAS mutant pts to matched-case control HRAS wild type (wt) HNSCC pts. Information on subsequent lines of therapy for HRAS mutant and wt pts will also be collected. AIM-HN will enroll at least 59 pts (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) who are refractory or have relapsed from at least one prior line of systemic platinum-based therapy and have measurable disease by RECIST 1.1. AIM-HN pts must have tumors with >35% HRAS mutant variant allele frequency (VAF) or >20% VAF if serum albumin is >3.5 g/l. AIM-HN pts will receive treatment with tipifarnib at 600 mg bid on days 1-7 and 14-21 of 28-day cycles. Using Simon's Two-Stage Minimax design, if true ORR is > 30%, the study will have 80% power to detect ORR > 15% at 0.025 significance level. Both interim (after first 31 pts) and final analysis, 2-sided 95% CI on ORR, will be performed on the modified intent to treat population. The SEQ-HN observational cohort will enroll ~225 control pts who will receive standard of care treatment. A subset of SEQ-HN pts will be matched to the HRAS mutant AIM-HN pts according to defined patient characteristics and compared for responses to therapy. Clinical trial information: NCT02383927 .

scholarly journals Rate of Recovery and Symptomatic Efficacy of a Polyherbal AYUSH Formulation in the Treatment of SARS CoV-2 disease: A Single-arm trial

2021 ◽  
Author(s):  
Divya Kanchibhotla ◽  
Prateek Harsora ◽  
Saumya Subramanian ◽  
Ravi reddy ◽  
Hari Venkatesh
Keyword(s):  
Standard Of Care ◽  
Rt Pcr ◽  
Open Label ◽  
Subjective Analysis ◽  
Polyherbal Formulation ◽  
Care Treatment ◽  
Symptomatic Management ◽  
Standard Of Care Treatment ◽  
Rate Of Recovery ◽  
Time Required

Abstract Background: The COVID-19 pandemic, caused by the human coronavirus SARS CoV-2, has led to millions of deaths across the globe. Not only is the SARS CoV-2 virus highly infectious, it also mutates very easily. This creates additional challenges for development of robust therapeutic solutions. Along with modern system of healthcare, there is a definite need for exploring natural plant based antiviral compounds directed against the SARS CoV-2 virus. Objective: The present observational study investigates the efficacy of an Ayurvedic polyherbal formulation of 19 ingredients, NOQ19, in the management of COVID-19. Methodology: A single arm, single centric, open label study design was adopted for this feasibility study. 161 RT-PCR positive COVID-19 patients were enrolled. The enrolled participants were provided the Ayurvedic intervention, 2 tablets of NOQ19, thrice daily along with the standard of care treatment. Follow up COVID-19 RT- PCR tests were conducted on Day 5, Day 10 and Day 14, or until the patient turned negative. The time required for testing negative on the RT-PCR test or becoming asymptomatic was noted. Results: A subjective analysis demonstrated that 74% of patients turned RT-PCR negative within 5 days of taking NOQ19. Additionally, 98% of the subjects turned RT-PCR Negative on Day 10 after taking NOQ19 in addition to the standard of care treatment of Vitamin C , Zinc and antipyretic (as necessary). None of the participants reported any adverse or side effects to the medication.Conclusion: NOQ19 Ayurvedic polyherbal formulation can be an effective and safe option for the symptomatic management of COVID-19.

scholarly journals A Phase 1/1b Open-Label, Multicenter, Two-Part Study of SETD2 Inhibitor EZM0414 in Patients with Relapsed/Refractory Multiple Myeloma or Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1679-1679
Author(s):  
Paul G. Richardson ◽  
Ruben Niesvizky ◽  
Jay Yang ◽  
Neelu Yadav ◽  
Helen Hsu ◽  
...  
Keyword(s):  
Stock Options ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Standard Of Care ◽  
Phase 2 ◽  
Open Label ◽  
Large B Cell Lymphoma ◽  
Phase 1B

Abstract Background: Multiple myeloma (MM) is a heterogeneous disease of monoclonal plasma cells. More than 40% of patients with MM harbor translocations of the immunoglobulin heavy chain (IGH) gene on chromosome 14, leading to overexpression of putative oncogenes which can ultimately lead to plasma cell-derived, post-malignancy MM. One such translocation, t(4;14), is seen in 15% of patients and juxtaposes IGH control elements with two genes on chromosome 4, FGFR3 and MMSET. Patients harboring the (4;14) translocation have a poor response to standard of care therapies and an overall poor prognosis. MMSET expression has been confirmed as a driver in t(4;14) MM pathogenesis, but MMSET inhibitors have not yet been successfully developed in the clinic. Since MMSET generates the substrate for Su(var)3-9, enhancer of zeste, trithorax domain-containing 2 (SETD2) activity, SETD2 inhibition offers promise for targeting the underlying oncogenic mechanism in t(4;14) MM. Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in the United States, with a 5-year relative survival rate of 53% in patients diagnosed with stage IV DLBCL. Given the poor survival outcomes and low remission rates for patients with relapsed or refractory (R/R) DLBCL, there is a need for better treatment options. Although SETD2 mutations are described in DLBCL, the mechanism of action of SETD2 inhibitors remains unclear. EZM0414 is a potent and selective, orally bioavailable small-molecule inhibitor of SETD2. Preclinical data have demonstrated antitumor activity of EZM0414 in both t(4;14) and non-t(4;14) MM and DLBCL models. This study (enrollment scheduled to begin Q3 2021) will evaluate the safety and efficacy of EZM0414 when administered as monotherapy in patients with R/R MM with or without t(4;14), or with R/R DLBCL. Study Design and Methods: This first-in-human, 2-part, multicenter, open-label study will enroll patients aged ≥18 years with R/R MM who have received prior treatment with immune modulators, proteasome inhibitors, and anti-CD38 therapy, or who are intolerant to established therapies known to provide clinical benefit in MM, or with R/R DLBCL who have received at least 2 prior lines of therapy, including treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH); rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyper CVAD); or other standard of care therapies. Patients eligible for autologous stem cell transplantation will be excluded from this study. The first part of the study will be a phase 1 dose escalation study using a Bayesian optimal interval design to evaluate the safety and tolerability of EZM0414 in patients with R/R MM with or without t(4;14), or with R/R DLBCL. Six dose levels of 100, 200, 300, 400, 600, and 900 mg administered once daily will be tested. Patients will be enrolled and treated in a cohort size of 3, and up to 36 patients will be enrolled to evaluate at least 10 patients at the maximum tolerated dose (MTD). The MTD will be selected at the dose level with a target dose-limiting toxicity rate ≤25%. The second part of the study (phase 1b) will be a dose expansion at the MTD in patients with R/R MM with or without t(4;14), or with R/R DLBCL using the Bayesian optimal phase 2 design. Dose expansion will include 3 cohorts of up to 20 patients each. Cohort 1 will enroll patients with t(4;14)-positive R/R MM, cohort 2 will enroll patients with t(4;14)-negative R/R MM, and cohort 3 will enroll patients with R/R DLBCL. The primary endpoints will be determining safety, dose-limiting toxicities, the MTD, and a recommended phase 2 dose. Secondary endpoints include the objective response rate, progression-free survival, and duration of response. Exploratory endpoints include a pharmacokinetic/pharmacodynamic profile analysis and the determination of mechanism of action biomarkers, such as histones and histone methylation. The study design will include a futility assessment in the phase 1b part of the study, which will be initiated when clinical data from the first 10, 15, and 20 enrolled patients in the expansion cohort are available. Disclosures Richardson: Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Secura Bio: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Regeneron: Consultancy; Celgene/BMS: Consultancy, Research Funding; AbbVie: Consultancy; Sanofi: Consultancy; Protocol Intelligence: Consultancy; Oncopeptides: Consultancy, Research Funding. Niesvizky: BMS: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Yang: Epizyme, Inc.: Current Employment, Other: May own stock/options. Yadav: Epizyme, Inc.: Current Employment, Current holder of stock options in a privately-held company. Hsu: Epizyme, Inc.: Current Employment, Current holder of stock options in a privately-held company. Flowers: Iovance: Research Funding; Adaptimmune: Research Funding; Guardant: Research Funding; Denovo: Consultancy; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; Kite: Research Funding; Spectrum: Consultancy; Biopharma: Consultancy; SeaGen: Consultancy; Pharmacyclics/Janssen: Consultancy; Epizyme, Inc.: Consultancy; Acerta: Research Funding; 4D: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Nektar: Research Funding; Sanofi: Research Funding; Morphosys: Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Janssen: Research Funding; National Cancer Institute: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Cellectis: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; BeiGene: Consultancy; Xencor: Research Funding; TG Therapeutics: Research Funding; EMD: Research Funding; Burroughs Wellcome Fund: Research Funding; Ziopharm: Research Funding; Pharmacyclics: Research Funding.

Phase I pilot study of RRx-001 + nivolumab in patients with traditionally non-checkpoint inhibitor-responsive cancers (PRIMETIME).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15119-e15119
Author(s):  
Corey Carter ◽  
Scott Caroen ◽  
Bryan Oronsky ◽  
Mary Flanagan Quinn ◽  
Jeannie Williams ◽  
...  
Keyword(s):  
Adverse Event ◽  
Pilot Study ◽  
Dose Level ◽  
Phase 1 ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Preliminary Evidence ◽  
Open Label ◽  
Voluntary Withdrawal ◽  
Main Adverse Event

e15119 Background: RRx-001 is a minimally toxic small molecule that downregulates CD47 via Myc inhibition and repolarizes tumor-associated macrophages (TAMs). A phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced traditionally non-immunogenic cancers and no standard options. Methods: This single arm, open-label pilot study (NCT02518958) was designed to evaluate the safety profile of RRx-001 + nivolumab in patients with advanced malignancies. A 3+3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, 12 patients received treatment for 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events occurring within 16 weeks of the first dose of RRx-001 + nivolumab were characterized according to CTCAE v4.03. Results: 12 patients received > 1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no dose-limiting toxicities. The main adverse event related to RRx-001 was pain on infusion (33.3%). The main adverse event related to the combination was pseudoprogression (larger tumors in symptomatically improved patients) (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). Objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of > SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination. Conclusions: RRx-001 + nivolumab was well-tolerated with preliminary evidence of anti-cancer activity in non-immunogenic cancers. Further analyses with a larger sample size are required to confirm activity. Clinical trial information: NCT02518958 .

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