First-in-human dose escalation and food effect study of oral ONC206 in adults with recurrent primary CNS neoplasms.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2072-TPS2072
Author(s):  
Brett James Theeler ◽  
Jinkyu Jung ◽  
Eric Burton ◽  
Heather Leeper ◽  
Jing Wu ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Food Effect ◽  
Expression Profiles ◽  
Objective Response ◽  
Recurrent Glioblastoma ◽  
Cns Tumors ◽  
Open Label ◽  
Who Grade ◽  
Human Dose ◽  
Cns Neoplasms

TPS2072 Background: The majority of recurrent CNS tumors lack effective systemic therapy options following surgical resection and adjuvant radiotherapy. ONC201, the founding member of the imipridone class of small molecules, has induced durable tumor regressions in patients with diffuse midline glioma, H3 K27M-mutant (DMG H3K27M). ONC206, the second imipridone to enter clinical development, is a DRD2 antagonist and ClpP agonist that exhibits differentiated receptor pharmacology and gene expression profiles in tumors relative to ONC201. The compound is orally bioavailable, penetrates the blood-brain barrier, and exhibits anti-cancer efficacy without toxicity in several preclinical cancer models with pronounced efficacy in myc-overexpressing CNS tumors. Methods: A first-in-human, open label, dose escalation, and food effect Phase I study of oral ONC206 (NCT04541082) is currently enrolling. Patients must be 18 years or older and diagnosed with a recurrent, primary CNS neoplasm. Eligible diseases include recurrent glioblastoma, WHO Grade 2 and 3 infiltrating glial neoplasms, DMG H3K27M, ependymoma, medulloblastoma, malignant meningiomas, and other rare primary CNS neoplasms. Dose escalation, initially with weekly dosing, will follow a standard 3+3 design. After the MTD is established, a food effect cohort will enroll with a balanced, single-dose, two-arm, two-period, crossover design. The primary endpoint is to determine DLT during the first 28-day cycle. Secondary endpoints will include objective response rate by RANO criteria, overall and progression-free survival, and disease control rate. Exploratory biomarker analyses based on preclinical correlations with efficacy will include DRD2, DRD2 dimer, ClpP, DRD5, c-myc, and n-myc expression. Clinical trial information: NCT04541082.

scholarly journals Phase III Study of Enzastaurin Compared With Lomustine in the Treatment of Recurrent Intracranial Glioblastoma

2010 ◽  
Vol 28 (7) ◽  
pp. 1168-1174 ◽  
Author(s):  
Wolfgang Wick ◽  
Vinay K. Puduvalli ◽  
Marc C. Chamberlain ◽  
Martin J. van den Bent ◽  
Antoine F. Carpentier ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Objective Response ◽  
Progression Free Survival ◽  
Well Being ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Serious Adverse Events ◽  
Who Grade

PurposeThis phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma (WHO grade 4).Patients and MethodsPatients were randomly assigned 2:1 to receive 6-week cycles of enzastaurin 500 mg/d (1,125-mg loading dose, day 1) or lomustine (100 to 130 mg/m2, day 1). Assuming a 45% improvement in progression-free survival (PFS), 397 patients were required to provide 80% power to achieve statistical significance at a one-sided level of .025.ResultsEnrollment was terminated at 266 patients (enzastaurin, n = 174; lomustine, n = 92) after a planned interim analysis for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 months; hazard ratio [HR] = 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 months; HR = 1.20; 95% CI, 0.88 to 1.65), and 6-month PFS rate (P = .13) did not differ significantly between enzastaurin and lomustine, respectively. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, respectively. Time to deterioration of physical and functional well-being and symptoms did not differ between arms (HR = 1.12; P = .54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Eleven patients treated with enzastaurin died on study (four because of AEs; one was drug-related). All four deaths that occurred in patients receiving lomustine were disease-related. Grade 3 to 4 hematologic toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P ≤ .001).ConclusionEnzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma.

scholarly journals CTIM-03. PHASE II STUDY OF REGORAFENIB IN BEVACIZUMAB REFRACTORY RECURRENT GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii33-ii33
Author(s):  
Yasmeen Rauf ◽  
Cathy Schilero ◽  
David Peereboom ◽  
Manmeet Ahluwalia
Keyword(s):  
Dose Escalation ◽  
Therapeutic Option ◽  
Objective Response ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Weekly Dose ◽  
Cellular Functions ◽  
Molecule Inhibitor ◽  
Secondary Endpoints ◽  
Magnetic Resonance Imaging Mri

Abstract BACKGROUND Most patients with glioblastoma (GBM) receive bevacizumab as part of their treatment. There is no good therapeutic option after bevacizumab failure. Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic activity as measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging (MRI). Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. METHODS Patients with progression of GBM after treatment with Bevacizumab will be eligible for the study. Oral administration of Regorafenib at 160 mg once daily will be administered for 3 weeks on /1 week off. Weekly dose escalation of regorafenib from 80 mg to 160 mg/day will be employed as per the Redos strategy. Patients start the treatment 80 mg/day in week 1, with weekly dose escalation to 120 mg in week 2, then 160 mg week in 3 if no significant drug-related toxicities are observed. They will be continued on treatment with Regorafenib 160 md /day till tumor progression or toxicity. They will get MRI brain every 4 weeks during the study. RESULTS Primary endpoint is median Overall survival. Secondary endpoints include progression free survival at 6 months and the median time to progression and objective response rate using the modified RANO criteria. The overall safety and tolerability of regorafenib by CTCAE version 5.0. will also be reported. CONCLUSION This is an ongoing clinical trial.

scholarly journals RTID-05. INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF VORASIDENIB (AG-881) VS PLACEBO IN PATIENTS WITH RESIDUAL/RECURRENT GRADE II GLIOMA WITH AN ISOCITRATE DEHYDROGENASE 1/2 (IDH1/2) MUTATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii194-ii194
Author(s):  
Ingo Mellinghoff ◽  
Martin van den Bent ◽  
Jennifer Clarke ◽  
Elizabeth Maher ◽  
Katherine Peters ◽  
...  
Keyword(s):  
High Risk ◽  
Dose Escalation ◽  
Objective Response ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
High Risk Population ◽  
Low Grade ◽  
Who Grade ◽  
Free Survival ◽  
Grade Ii

Abstract BACKGROUND Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options are surgery followed by observation (“watch and wait”) for patients with lower risk for disease progression or postoperative chemoradiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (mIDH1/2) occur in approximately 80% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate. Vorasidenib, an oral, potent, reversible, brain-penetrant pan-inhibitor of mIDH1/2, was evaluated in 76 patients with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at daily doses below 100 mg. Preliminary clinical activity was observed in non-enhancing glioma patients in both studies, with an objective response rate (ORR) of 18.2% and median progression-free survival of 31.4 months in the dose escalation study. METHODS Approximately 366 patients will be randomized 1:1 to vorasidenib (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria: age ≥ 12 years; grade II oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed mIDH1/2 status; ≥ 1 surgery for glioma with most recent ≥ 1 year but ≤ 5 years before randomization, and no other anticancer therapy; Karnofsky performance status ≥ 80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the vorasidenib arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint: progression-free survival assessed by independent review. Secondary endpoints: safety and tolerability, tumor growth rate assessed by volume, ORR, overall survival, and quality of life. Clinical data will be reviewed regularly by an independent data monitoring committee. The study is currently enrolling patients in the US, with additional countries planned (NCT04164901).

A phase Ib/II, multicenter, open-label, dose-escalation, and dose-expansion study evaluating trastuzumab deruxtecan (T-DXd, DS-8201) monotherapy and combinations in patients with HER2-overexpressing gastric cancer (DESTINY-Gastric03).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS261-TPS261
Author(s):  
Yelena Y. Janjigian ◽  
Natasha Viglianti ◽  
Feng Liu ◽  
Ariadna Mendoza-Naranjo ◽  
Liz Croydon
Keyword(s):  
Gastric Cancer ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Gastric Cancer ◽  
Her2 Status ◽  
Open Label ◽  
Phase 1B

TPS261 Background: For patients (pts) with HER2-overexpressing metastatic gastric cancer, trastuzumab + chemotherapy is a standard first-line option but provides only a modest overall survival (OS) benefit vs chemotherapy. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload. Results from a phase 1 trial showed promising antitumor activity (confirmed objective response rate [ORR], 43.2%) in pts with heavily pretreated HER2+ metastatic gastric cancer who received T-DXd (5.4 or 6.4 mg/kg; Shitara K, et al. Lancet Oncol. 2019;20:827-836). Here we describe the phase 1b/2 DESTINY-Gastric03 trial (NCT04379596) evaluating T-DXd monotherapy and combinations in pts with HER2-overexpressing gastric cancer. Methods: This is an open-label, multicenter, 2-part, phase 1b/2 study in pts with HER2-overexpressing (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization positive) locally advanced, unresectable or metastatic gastric or gastroesophageal junction cancer. In part 1 (dose escalation), pts who had received prior trastuzumab-containing therapy will be assigned to 1 of 5 arms: (1) T-DXd + 5-fluorouracil (5-FU); (2) T-DXd + capecitabine (C); (3) T-DXd + durvalumab; (4) T-DXd + 5-FU or C + oxaliplatin (Ox); or (5) T-DXd + 5-FU or C + durvalumab. In part 2 (dose expansion), pts with no prior treatment for metastatic disease will be randomized across 4 arms: (1) T-DXd; (2) trastuzumab + 5-FU or C + Ox or cisplatin; (3) T-DXd + 5-FU or C ± Ox; or (4) T-DXd + 5-FU or C + durvalumab. In part 2, pts will be stratified by HER2 status. Primary endpoints are safety, determination of recommended phase 2 doses (part 1), and investigator-assessed confirmed ORR per RECIST v1.1 (part 2). Secondary endpoints include confirmed ORR (part 1), disease control rate, duration of response, progression-free survival (all per investigator), OS, safety (part 2), pharmacokinetics, and immunogenicity. Clinical trial information: NCT04379596.

scholarly journals Axitinib plus avelumab in the treatment of recurrent glioblastoma: a stratified, open-label, single-center phase 2 clinical trial (GliAvAx)

2020 ◽  
Vol 8 (2) ◽  
pp. e001146
Author(s):  
Gil Awada ◽  
Laila Ben Salama ◽  
Jennifer De Cremer ◽  
Julia Katharina Schwarze ◽  
Lydia Fischbuch ◽  
...  
Keyword(s):  
Adverse Events ◽  
Group Performance ◽  
Performance Status ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Synergistic Activity ◽  
Open Label ◽  
Corticosteroid Dose

BackgroundNo treatment demonstrated to improve survival in patients with recurrent glioblastoma (rGB) in a randomized trial. Combining axitinib with the programmed cell death ligand 1 blocking monoclonal antibody avelumab may result in synergistic activity against rGB.MethodsAdult patients with rGB following prior surgery, radiation therapy and temozolomide chemotherapy were stratified according to their baseline use of corticosteroids. Patients with a daily dose of ≤8 mg of methylprednisolone (or equivalent) initiated treatment with axitinib (5 mg oral two times per day) plus avelumab (10 mg/kg intravenous every 2 weeks) (Cohort-1). Patients with a higher baseline corticosteroid dose initiated axitinib monotherapy; avelumab was added after 6 weeks of therapy if the corticosteroid dose could be tapered to ≤8 mg of methylprednisolone (Cohort-2). Progression-free survival at 6 months (6-m-PFS%), per immunotherapy response assessment for neuro-oncology criteria, served as the primary endpoint.ResultsBetween June 2017 and August 2018, 54 patients (27 per cohort) were enrolled and initiated study treatment (median age: 55 years; 63% male; 91% Eastern Cooperative Oncology Group Performance Status 0–1). Seventeen (63%) patients treated in Cohort-2 received at least one dose of avelumab. The 6-m-PFS% was 22.2% (95% CI 6.5% to 37.9%) and 18.5% (95% CI 3.8% to 33.2%) in Cohort-1 and Cohort-2, respectively; median overall survival was 26.6 weeks (95% CI 20.8 to 32.4) in Cohort-1 and 18.0 weeks (95% CI 12.5 to 23.5) in Cohort-2. The best objective response rate was 33.3% and 22.2% in Cohort-1 and Cohort-2, respectively, with a median duration of response of 17.9 and 19.0 weeks. The most frequent treatment-related adverse events were dysphonia (67%), lymphopenia (50%), arterial hypertension and diarrhea (both 48%). There were no grade 5 adverse events.ConclusionThe combination of avelumab plus axitinib has an acceptable toxicity profile but did not meet the prespecified threshold for activity justifying further investigation of this treatment in an unselected population of patients with rGB.

Lazertinib, a 3rd generation EGFR-TKI, in patients with EGFR-TKI resistant NSCLC: Updated results of phase I/II Study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9037-9037 ◽  
Author(s):  
Myung-Ju Ahn ◽  
Ji-Youn Han ◽  
Sang-We Kim ◽  
Ki Hyeong Lee ◽  
Dong-Wan Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Egfr Mutations ◽  
Duration Of Treatment ◽  
Open Label ◽  
T790m Mutation ◽  
Dose Levels ◽  
Egfr Tki

9037 Background: Lazertinib (YH25448) is a highly mutant-selective, irreversible 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets the activating EGFR mutations (Del19 and L858R), as well as the T790M mutation, while sparing wild type. We report the updated results from a Phase I/II study of lazertinib (NCT03046992). Methods: Patients with advanced and metastatic NSCLC who had progressed after treatment with standard EGFR-TKIs with/without asymptomatic brain metastases (BM) were enrolled in an open-label, multicenter, phase I/II study with dose-escalation and expansion cohorts. Lazertinib was administered once daily at doses between 20 to 320 mg in a 21-day cycle. Patients were assessed for safety, tolerability and efficacy. T790M mutation was required in the dose-expansion cohorts. Results: As of 26 Nov 2018, a total of 127 patients were enrolled. The dose-escalation cohort included 38 patients administered with 20 to 320 mg across 7 dose levels, and 89 patients in the dose-expansion cohort were administered with 40 to 240 mg across 5 dose levels. No dose-limiting toxicities were observed. The median duration of treatment was 9.7 months and 58 patients are still ongoing. The objective response rate (ORR) was 60% in all patients, 64% in T790M+ patients, and 37% in T790M- patients by investigators assessment. In BM patients with measurable lesion (n = 14), the intracranial ORR was 50%. The median progression-free survival (PFS) was 8.1 months in all patients, 9.5 months in T790M+ patients, and 5.4 months in T790M- patients. Subgroup analysis showed that ORR was 65% and PFS was 12.2 months in T790M+ patients with ≥ 120 mg (n = 62). The most common treatment-emergent adverse events (TEAEs) were pruritus (27%), rash (24%), constipation (20%), decreased appetite (19%) and diarrhea (14%). TEAEs leading to dose discontinuation were observed in 3% of patients. Drug related TEAEs of grade ≥ 3 was observed in 3% of the patients. Conclusions: Lazertinib was safe, well-tolerated and exhibits promising systemic and intracranial antitumor activity in EGFR T790M+ NSCLC patients. Dose extension cohorts in the 1st and 2nd line settings are underway at 240 mg dose. Clinical trial information: NCT03046992.

A phase I dose-escalation and expansion study of intratumoral CV8102 as single-agent or in combination with anti-PD-1 antibodies in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3096-3096
Author(s):  
Thomas Eigentler ◽  
Franz G Bauernfeind ◽  
Jürgen C. Becker ◽  
Peter Brossart ◽  
Michael Fluck ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Dose Escalation ◽  
Single Agent ◽  
Objective Response ◽  
Study Drug ◽  
Tumor Growth Inhibition ◽  
Open Label ◽  
Dose Levels

3096 Background: CV8102 is a non-coding, non-capped RNA that activates the innate (via TLR7/8, RIG-I) and adaptive immunity dose-dependently. CV8102 injected intratumorally (i.t.), as a single agent or combined with systemic anti-PD-1 antibody (Ab) led to tumor growth inhibition in animal models and showed synergism with PD-1 blockade. Methods: An open-label, cohort-based, dose escalation and expansion study in patients with advanced cutaneous melanoma (cMEL), cutaneous squamous cell carcinoma (cSCC), head and neck squamous cell carcinoma (hnSCC) or adenoid cystic carcinoma (ACC) is ongoing investigating i.t. CV8102 as single agent and in combination with anti-PD-1 antibodies. [NCT03291002]. Results: As of December 2019, 23 patients in the cohort A (single agent) and 13 patients in cohort C (combination with anti-PD-1 Ab) were exposed to at least one dose of CV8102 at dose levels of 25-600 µg (single agent) and 25-450 µg (combination). No dose limiting toxicities (DLTs) were observed within the first two weeks of study drug treatment. Most frequent TEAEs were G1/2 fatigue, fever, chills and headache. 4 (17%) patients (pts) in cohort A and 3 (23%) pts in cohort C experienced related G3 TEAEs that were manageable with supportive treatment (liver enzyme increases (3), abscess at injection site (1), hypertension (1), asymptomatic elevation of pancreatic enzymes (2)). In cohort A, 2 cMEL patients experienced an objective response according to RECIST 1.1 (1 CR in a PD-1 naïve pt and 1 PR in a PD-1 refractory pt) and 2 further pts (cMEL, hnSCC) showed SD with shrinkage of tumor lesions. Conclusions: CV8102 i.t. was well tolerated without dose limiting toxicities to date and showed evidence of single agent activity. Updated results on safety, efficacy and serum biomarkers will be presented. Clinical trial information: NCT03291002 .

A phase I, open-label, dose-escalation trial of BI 1701963 as monotherapy and in combination with trametinib in patients with KRAS mutated advanced or metastatic solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3651-TPS3651 ◽  
Author(s):  
Eelke Gort ◽  
Melissa Lynne Johnson ◽  
Jimmy J. Hwang ◽  
Shubham Pant ◽  
Ulrich Dünzinger ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Retinal Pigment ◽  
Objective Response ◽  
Active Form ◽  
Open Label ◽  
Retinal Pigment Epithelial Detachment ◽  
Kras Mutations ◽  
Part C ◽  
Recist 1.1 ◽  
Number Of Patients

TPS3651 Background: Activating mutations of KRAS drive many types of cancer. Activation of KRAS relies on guanine nucleotide exchange factors, such as SOS1, to mediate exchange of GDP for GTP. BI 1701963 is a small-molecule protein–protein interaction inhibitor that prevents the interaction between KRAS and SOS. Binding of BI 1701963 to the catalytic site of SOS1 inhibits binding of SOS1 to RAS–GDP, thereby hindering the exchange from RAS–GDP (inactive form) to RAS–GTP (active form). In preclinical studies this has been shown to lead to cytostasis in cancer cells addicted to KRAS signaling. Methods: NCT04111458 is a first-in-human trial of BI 1701963 in patients aged ≥18 years with tumors harboring KRAS mutations. Primary objectives are to determine the maximum tolerated dose (MTD) and recommended Phase II dose of BI 1701963 as monotherapy and in combination with trametinib, based on dose-limiting toxicities (DLTs). Secondary objectives are to evaluate safety, tolerability, pharmacokinetics/-dynamics and preliminary efficacy. The study will have two arms (mono- and combination therapy), and be divided into dose escalation (Part A), confirmation (Part B) and expansion (Part C, combination only) phases. Inclusion criteria include activating KRAS mutation, ≥1 evaluable lesion (RECIST 1.1), ECOG PS ≤1 and adequate organ function. Exclusion criteria include history of: RAS, MAPK or SOS1 targeting therapies; retinal vein occlusion; retinal pigment epithelial detachment; and decreased cardiac function. Parts B and C will be conducted in patients with advanced NSCLC. Treatment will continue until confirmed clinical benefit, defined toxicities, or withdrawal of consent. The primary endpoints are: Part A, the MTD, and the number of patients with DLTs during Cycle 1; Part B (monotherapy), the number of patients with DLTs; Part C, objective response (OR, RECIST 1.1). Starting doses of BI 1701963 in Part A will be 50 mg once daily (QD) orally (monotherapy) and 100 mg QD (combination, once proved safe as monotherapy) and will be escalated until the MTD is reached. The starting dose of trametinib will be 1 mg QD, escalated to the MTD or a max. of 2 mg QD. Dose cohorts will include ≥3 patients, with two therapeutic relevant doses (TRDs) established in each arm. In Part B, patients will be randomized to groups receiving one of the TRDs. If an OR is observed at a TRD in the combination arm, additional patients will be recruited into expansion cohorts receiving the relevant dose. As of Feb 11, 2020 three patients have been treated. Clinical trial information: NCT04111458 .

Safety and Efficacy of Daratumumab with Lenalidomide and Dexamethasone in Relapsed or Relapsed, Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 84-84 ◽  
Author(s):  
Torben Plesner ◽  
Hendrik-Tobias Arkenau ◽  
Henk M. Lokhorst ◽  
Peter Gimsing ◽  
Jakub Krejcik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
M Protein ◽  
Open Label ◽  
Advisory Committees ◽  
Dose Escalation Study ◽  
Human Dose

Abstract Background: Daratumumab (DARA) (HuMax™-CD38), a human IgG1κ monoclonal antibody effectively mediates destruction of CD38-expressing malignant plasma cells. In the first-in-human dose-escalation study, 42% of heavily pretreated patients with relapsed, or relapsed, refractory (RR) multiple myeloma (MM) treated with DARA alone (≥4mg/kg) achieved partial response (PR) and 25% had minimal response (MR) (modified IMWG guidelines) (1). In preclinical studies, DARA + lenalidomide (LEN) enhanced killing of MM cells in vitro (2). We evaluated safety, pharmacokinetics (PK) and efficacy of DARA + LEN + low-dose dexamethasone (DEX) in patients with relapsed or RR MM. Methods: This ongoing phase I/II open-label multicenter study consisted of 2 parts: Part1 was dose-escalation study in which patients (≥ 18 years old) with life expectancy ≥3 months and ECOG status 0, 1 or 2 received DARA+LEN+DEX (DARA [2-16 mg/kg] per week [8 weeks], twice a month [16 weeks], then, once monthly until disease progression, unmanageable toxicity or 24 months in total; LEN [25 mg PO day 1 through 21 of 28-days cycles]; DEX [40 mg] once weekly). Part 2 was cohort expansion study which explored the testing of maximum tolerated DARA dose (MTD) (16 mg/kg) determined in part 1 along with LEN (25 mg mg PO day 1 through 21 of 28-days cycles) and DEX (40 mg) once weekly. Results: Data from 22 patients (13 patients [fully enrolled] from part 1 and 9 patients from part 2, [ongoing enrollment]) were presented at ASCO earlier this year (3). These results demonstrated that the most frequent (>30% patients) adverse events (AEs) were neutropenia and diarrhea; no dose limiting toxicities (DLTs) were reported. Infusion reactions (grade 1 and 2) were reported in 4 patients. 8 serious AEs were reported, all assessed as unrelated to DARA. MTD was not reached. DARA+LEN+DEX PK-profile was similar to DARA alone suggesting LEN and DEX do not affect the DARA PK-profile. Available preliminary efficacy data from 20 patients demonstrated marked decrease in M-protein in all patients; 15/20 patients achieved PR or better, 3/20 with CR, 6/20 with VGPR. Median time to response was 4.3 weeks (range: 2.1-11.3). Overall response rate (ORR) was 75% (15/20) combining all patients in part 1 and 2 and 92.3% (12/13) for part 1 patients, who had at least 2 months of follow-up or discontinued earlier. Conclusions: DARA+LEN+DEX has favorable safety profile with manageable toxicities in relapsed and RR MM. Encouraging early activity is seen with marked reduction in M-protein and majority of the patients (~75%) achieved PR or better. Results of approximately 30 patients from part 2 with at least 2 months of treatment exposure and 10 patients (out of 30 patients) with shortened duration of infusion will be presented. References Lokhorst et. al., EHA 2013 abstract #8512 van der Veer et. al., Haematologica 2011;96(2):284-90 Plesner et. al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8533). Disclosures Plesner: Genmab: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees. Lokhorst:Celgene: Research Funding; J&J: Research Funding; Genmab: Research Funding. Minnema:Janssen: Consultancy, Honoraria. Laubach:Onyx: Research Funding; Novartis: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Ahmadi:Janssen: Employment. Yeh:Janssen: Employment. Guckert:Janssen: Employment. Feng:Janssen: Employment. Brun:Genmab: Employment. Lisby:Genmab: Employment. Basse:Genmab: Employment. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding.

scholarly journals PC3 - 151 Toca 5: A Phase 2/3 Randomized, Open-Label Study of Toca 511, a Retroviral Replicating Vector, Combined with Toca FC versus Standard of Care in Patients Undergoing Planned Resection for Recurrent Glioblastoma (GBM) or Anaplastic Astrocytoma (AA) (NCT02414165)

2016 ◽  
Vol 43 (S4) ◽  
pp. S17-S17
Author(s):  
G. Zadeh ◽  
D. Bota ◽  
D. Cachia ◽  
J. Landolfi ◽  
D. Schiff ◽  
...  
Keyword(s):  
Phase 1 ◽  
Objective Response ◽  
Unmet Need ◽  
Suppressor Cells ◽  
Standard Of Care ◽  
Immune Monitoring ◽  
Recurrent Glioblastoma ◽  
Phase 2 ◽  
Open Label ◽  
Dismal Prognosis

Recurrent GBM and AA have a dismal prognosis and a high unmet need for effective therapies. Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that encodes the transgene cytosine deaminase (CD). Toca 511 selectively infects, persists and spreads in tumor. Subsequent oral administration of 5-fluorocytosine (Toca FC) produces 5-fluorouracil (5-FU) by CD within infected cells. 5-FU kills cancer cells and myeloid derived suppressor cells, inducing robust antitumor immune responses in animal models. Clinical data from phase 1 trials are consistent with this mechanism of action, and show extended survival compared to historical controls. Toca 5 is a multicenter, randomized, open-label Phase 2/3 trial of Toca 511 and Toca FC versus standard of care administered to patients undergoing resection for first or second recurrence of GBM or AA. Phase 2 will enroll 170 patients. Primary endpoint is overall survival (OS). Key secondary endpoints are safety, objective response rate, clinical benefit rate, progression-free survival, and landmark OS. Key inclusion criteria are age 18-75 years, histologically proven GBM or AA, measurable disease preoperatively of less than 5cm, candidate for equal or greater 80% resection of enhancing tumor based on pre-operative evaluation, and KPS equal or greater to 70. Assays for immune monitoring will be performed and molecular profiling of resected tumor samples will be correlated efficacy.

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