A first-in-human, multicenter, open-label, phase 1 study of ATOR-1017, a 4-1BB antibody, in patients with advanced solid malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2646-2646
Author(s):  
Gustav J. Ullenhag ◽  
Jeffrey Yachnin ◽  
Ana Carneiro ◽  
Emma Elison ◽  
Malin Carlsson ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Choroidal Melanoma ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Phase 1 Study ◽  
Solid Malignancies

2646 Background: ATOR-1017 is a human agonistic IgG4 antibody targeting the co-stimulatory receptor 4-1BB (CD137). It is developed to activate T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell killing. This is a first-in-human, multicenter, phase 1 study (NCT04144842). Methods: In this study, ATOR-1017 is administered intravenously every 21 days as a single agent to patients with solid malignancies. ATOR-1017 is administered until confirmed progressive disease, unacceptable toxicity or withdrawal of consent. The primary objective of the study is to determine the maximum tolerated dose, assessed by adverse events (AEs) and dose limiting toxicities (DLTs), and the recommended phase 2 dose. Secondary objectives include pharmacokinetics, immunogenicity and clinical efficacy, assessed with CT scans using response criteria for use in studies testing immunotherapeutics (iRECIST). The study uses a single cohort design for doses up to 40 mg, and thereafter a modified 3+3 design. Results: The first patient was dosed in December 2019; by 22 Jan 2021, twelve patients have been exposed to ATOR-1017. The following dose levels have been evaluated; 0.38 mg; 1.5 mg; 5 mg; 15 mg; 40 mg and 100 mg. Dose escalation is ongoing, and the 200 mg dose level is under evaluation. The maximum tolerated dose has not been reached. The following cancer types are included; ovarian cancer (n = 1), choroidal melanoma (n = 3), anal cancer (n = 1), cholangiocarcinoma (n = 1), gastrointestinal stromal tumor (n = 1), breast cancer (n = 1), pancreatic cancer (n = 1), adenoid cystic cancer (n = 1), malignant melanoma (n = 1), colorectal cancer (n = 1). Drug-related AEs were reported in 5 out of 12 patients; one patient experienced a grade 3, all others were grade 1 or 2. There have been two episodes each of chest pain (grades 2 and 3) and headache (grades 1 and 2). Single cases of pyrexia, upper abdominal pain, mouth ulceration, nausea, leukopenia, neutropenia, cytokine release syndrome (CRS), arthralgia, neck pain, and rash were also reported. No DLTs have been observed in the study to date. The median age of the patients were 48.5 years (range 34-76). Patients received a median of 2 prior lines of therapy (range 1-4). The median time on study were 15 weeks (range 0.14-51). Six patients are on study, and six patients have discontinued treatment. Reasons for discontinuation include; investigator decision (n = 1), confirmed disease progression (n = 1), withdrawal of consent (n = 1), death due to disease progression (n = 1) and other reason (n = 2). Preliminary PK data show dose-proportional kinetics up to 100 mg. Best response has been stable disease. Conclusions: ATOR-1017 is safe and well-tolerated up to 100 mg. Dose escalation continues and the current dose level is 200 mg. Clinical trial information: NCT04144842.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

A Phase 1 Study of Sequential Idarubicin + Cytarabine, Followed by Lenalidomide, in Patients with Previously Untreated Acute Myeloid Leukemia (AML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2600-2600 ◽  
Author(s):  
Jeffrey E. Lancet ◽  
Rami S. Komrokji ◽  
Daohai Yu ◽  
Anjali S. Advani ◽  
Tammy Searles ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Survival Data ◽  
Research Funding ◽  
Drug Exposure ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Open Label ◽  
Phase 1 Study ◽  
Simultaneous Exposure

Abstract Abstract 2600 Background: Lenalidomide (Len) is an immunodulatory agent with proven efficacy in lower-risk myelodysplastic syndromes (MDS) and with strong signals of single-agent activity in higher-risk MDS and AML patients (pts). Our preclinical data showed that Len antagonized cytarabine cytotoxicity with simultaneous exposure, while augmenting the effects of anthracyclines and cytarabine with sequential drug exposure. We initiated a phase 1 combination study in patients with AML investigating sequential standard induction chemotherapy followed by Len. Objectives: 1) to determine the safety and maximum tolerated dose (MTD) of Len following idarubicin/cytarabine induction. 2) to assess preliminary signs of efficacy of this regimen in adults with previously untreated AML. Methods: This was a multicenter, open-label, dose escalation phase 1 study with a 3+3 dosing design of idarubicin (12 mg/m2, day 1–3), cytarabine (100 mg/m2, CI day 1–7) + Len (starting dose 5 mg, day 8–21). Len dose was escalated in 5 mg increments up to a maximum of 25 mg/day. Eligibility included pts with AML age ≥60 years or age <60 with associated del 5/5q; or MDS/RAEB-2 with prior hypomethylating agent failure. Other inclusion criteria included: ECOG PS 0–2 and adequate end-organ function (including normal LVEF of ≥ 50%). Pts who achieved CR/CRi after 1 or 2 cycles of induction were eligible to receive post-remission idarubicin/cytarabine/Len (at the same dose level) for up to 2 cycles, followed by Len maintenance 10 mg/day for up to 12 months. The MTD cohort was expanded to 10 patients. Results: Of 23 enrolled and treated pts, 21 have completed at least 1 treatment cycle. Median age was 68 years (range 44–79); males: 18 (78%). Eleven pts had del 5/5q associated karyotype (10 of whom had complex karyotype), and 15 had secondary AML (including 8 who received prior hypomethylating agents). Len dose escalation reached 25mg/day, with MTD determined to be 20 mg/day. Dose-limiting toxicities occurred in 2 of 3 patients treated at Len 25 mg/day (grade 3 rash; grade 4 neutropenia and thrombocytopenia persisting beyond day 56) and in 1 of 8 patients treated at Len 20 mg/day (grade 4 cardiac ischemia). Only 1 of 21 (5%) patients died within 30 days of treatment initiation. The most common therapy-related non-hematologic toxicities (occurring in ≥ 20% of patients, the vast majority of which were grade 1–2) included: diarrhea (76%), infection/febrile neutropenia (71%), rash (62%), nausea (43%), pain (43%), hemorrhage (33%), fatigue (29%), and non-neutropenic fever (24%). Of the 20 patients evaluable for response, 7 achieved CR and 1 CRi, for an overall response rate (ORR) of 40%. Of 11 evaluable patients treated at the MTD (Len 20 mg/day) and higher, the ORR was 55%. CR occurred in 3 out of 10 (30%) patients with associated del 5/5q. Conclusion: Sequential idarubicin/cytarabine + Len was generally well-tolerated in a primarily older population of patients with previously untreated AML, with MTD of 20 mg/day for Len. Clinical activity in this poor-risk population appears promising at the MTD and higher. Further exploration of this regimen in older AML patients is warranted, with plans for a phase 2 expansion underway. Updated toxicity, response, and survival data will be presented. Disclosures: Lancet: Celgene: Research Funding. Off Label Use: Lenalidomide is approved for use in MDS. Its investigational role in AML will be discussed. Komrokji:Celgene: Honoraria, Research Funding, Speakers Bureau. Sekeres:Celgene: Advisory Board. List:Celgene: Consultancy.

A phase I study of MM-121 in combination with multiple anticancer therapies in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2609-2609 ◽  
Author(s):  
Monica Arnedos ◽  
Crystal Shereen Denlinger ◽  
Wael A. Harb ◽  
Olivier Rixe ◽  
John Charles Morris ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Clinical Benefit ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Clinical Benefit Rate

2609 Background: MM-121 is a fully human monoclonal antibody targeting the epidermal growth factor receptor family member ErbB3. ErbB3 has been implicated in driving cancer growth and in the development of resistance to conventional chemotherapies across multiple malignancies. Here we present results of an open-label, Phase 1, multicenter, non-randomized, dose-escalation trial which recently completed enrollment evaluating MM-121 in combination with one of the following chemotherapies: Gemcitabine (Arm A, n=11), carboplatin (Arm B, n=11), pemetrexed (Arm C, n=10), or cabazitaxel (Arm D, n=11). Methods: Patients were treated in a dose escalation “3+3” design to assess the safety, tolerability and pharmacokinetics (PK) of MM-121 administered weekly in combination with anticancer therapies in subjects with advanced cancer. Doses were escalated until the maximum tolerated dose (MTD) was identified or the combination was shown to be tolerable at the highest planned doses. Secondary objectives included: Determining the objective response rate, clinical benefit rate, PK and immunogenicity of MM-121. Data summarized are as of 1/17/2013 from a live database. Results: Overall, 43 patients, [22 (51%) female and 21 (49%) male] have been treated with a median treatment duration of 57 days (range 1-302). The median age was 59 years (range 42-84) and patients had received a median of four prior lines of therapy (range 0-13). Common (>20%) adverse events of any grade and causality across all arms included diarrhea (74%), nausea (54%), fatigue (51%), anemia (44%), vomiting (33%), hypokalemia (30%), decreased appetite (26%), thrombocytopenia (26%), peripheral edema (23%), neutropenia (21%), and constipation (21%). Four DLTs were observed: Two in combination with carboplatin (G4 thrombocytopenia and G3 rash), one with gemcitabine (G4 thrombocytopenia), and one with pemetrexed (G4 hyperuricemia). Overall 38 (88%) patients were evaluable for response and the overall clinical benefit rate (PR or SD >18 weeks), is 32% (12/38). Conclusions: MM-121 can be combined at its recommended single agent dose with standard doses of gemcitabine, pemetrexed, and cabazitaxel and adapted doses of carboplatin. Clinical trial information: NCT01447225.

421 Initial results of a phase 1 trial of RP2, a first in class, enhanced potency, anti-CTLA-4 antibody expressing, oncolytic HSV as single agent and combined with nivolumab in patients with solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A447-A447
Author(s):  
Francesca Aroldi ◽  
Joseph Sacco ◽  
Kevin Harrington ◽  
Anna Olsson-Brown ◽  
Pablo Nanclares ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Cytotoxic T Lymphocyte ◽  
Phase 1 ◽  
Single Agent ◽  
Open Label ◽  
Safety And Efficacy ◽  
Biodistribution Data ◽  
Biomarker Analysis ◽  
Hsv 1

BackgroundRP2 is an enhanced potency oncolytic HSV-1 expressing granulocyte-macrophage colony-stimulating factor (GM-CSF), a fusogenic protein (GALV-GP R-), and an anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody-like molecule which is being tested in an open-label, multicenter, phase 1 study alone and combined with PD-1 blockade (NCT04336241).MethodsThe objectives were to assess initial safety and efficacy and determine the recommended phase 2 dose (RP2D) of RP2 alone and combined with nivolumab. Patients were to be treated using a 3+3 dose escalation at two dose levels of up to 10 mL of RP2 Q2W up to 5 times (dose level 1: 105 PFU/mL then 4 doses of 106 PFU/mL; dose level 2: 106 PFU/mL then 4 doses of 107 PFU/mL). Following determination of the RP2D, additional HSV-1 seronegative patients were to be enrolled such that ≥3 had been dosed with RP2 at the RP2D, and a combination cohort of up to 30 patients dosed up to 8 times with RP2 at the RP2D combined with nivolumab (240 mg Q2W for 4 months from the second RP2 dose, then 480 mg Q4W for 20 months) opened. Lesions were injected directly or under imaging guidance used for visceral lesions. Tumor biopsies were obtained for biomarker analysis. Viral shedding and anti-HSV antibody titers were also monitored.ResultsSix HSV seropositive patients were enrolled in the dose-escalation phase with primarily Grade 1–2 adverse events, including febrile and other constitutional symptoms, local inflammation, and erythema observed. There were no DLTs requiring dose level expansion. The RP2D was selected as up to 10 mL of 106 PFU/mL followed Q2W by multiple doses of 107 PFU/mL. Of the six patients treated with single agent RP2, three (50%) have ongoing partial responses. Objective responses (including in uninjected tumors) were observed in patients with uveal melanoma (prior ipilumumab/nivolumab; extensive liver metastases), mucoepidermoid carcinoma (prior carboplatin/paclitaxel, bicalutamide, ceralasertib), and esophageal cancer (prior durvalumab, M6620, capecitabine, oxaliplatin, cisplatin, chemoradiation; liver and abdominal node metastases). Enrollment is underway in HSV seronegative patients and in combination with nivolumab. Updated data including biomarker and biodistribution data will be presented.ConclusionsThe Phase 1 clinical data supports the safety and efficacy of single agent RP2, including demonstration of uninjected tumor response in patients with difficult to treat advanced cancers. This data supports the hypothesis that anti-CTLA-4 delivered intra-tumorally through oncolytic virus replication, with accompanying antigen release and presentation, can provide potent anti-tumor effects.

scholarly journals Repurposing Leflunomide for Relapsed/Refractory Multiple Myeloma: Final Analysis of a Phase 1 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2007-2007
Author(s):  
Michael Rosenzweig ◽  
Joycelynne Palmer ◽  
Ni-Chun Tsai ◽  
Ralf Buettner ◽  
Lupe Duarte ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Dose Escalation ◽  
Clinical Benefit ◽  
Phase 1 ◽  
Single Agent ◽  
Study Drug ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Phase 1 Study

Abstract Introduction: Despite significant progress in the treatment of multiple myeloma (MM), the disease remains incurable and typically follows a pattern of multiple responses and relapses. In the relapsed/refractory MM setting (RRMM), outcomes for patients may be particularly discouraging. New treatments that are safe and effective are therefore of urgent need for this population. Since its FDA approval in 1998 for the treatment of rheumatoid arthritis, leflunomide has been used in over 300,000 patients worldwide. Leflunomide is hepatically cleared and has a favorable toxicity profile even when given over long periods. Its primary mechanism of action is inhibition of pyrimidine synthesis by targeting dihydroorotate dehydrogenase, thus achieving anti-proliferative effects on B and T lymphocytes. The anti-neoplastic potential of this agent has been studied in a number of pre-clinical tumor models. Leflunomide's immunoregulatory action may be related to functional inhibition of CD4+ effector T cells, including Th17 cells as well as dysregulation of T regulatory cells (Tregs). We found that leflunomide-treated C57BL/KaLwRij mice engrafted with 5TGM1 cells had more robust expansion of CD8+ cytotoxic T cells and subsequent decrease of CD4+ Tregs compared to untreated mice. We have also noted that leflunomide impairs growth of MM cells at least partly through inhibition of PIM kinases and c-Myc signaling. We present here final results from a phase 1 study of leflunomide in patients with RRMM. Methods: This single center, single agent, phase 1 dose-escalation trial was designed to determine the maximum tolerated dose of leflunomide in patients with RRMM. The trial implemented a modified rolling six phase 1 dose escalation design. The primary objectives were as follows: 1) to determine the maximum tolerated dose and recommended phase 2 dose of leflunomide; 2) to assess the safety and tolerably of leflunomide at each dose level by evaluation of toxicities. Leflunomide was administered at a loading dose of 100 mg daily for the first three days, then daily in 28-day cycles. The starting dose of daily leflunomide was 20 mg daily, with dose escalation in increments of 20 mg/day, up to 60 mg/day. Dose de-escalation in decrements of 10mg/day was planned. Results: A total of 12 patients have been enrolled starting in December 2015 and treated. The median age is 68 (range 48 - 85), and the median number of prior therapies is 5 (range: 3 - 14). Nine patients had prior autologous stem cell transplant. Double refractory (lenalidomide/bortezomib) disease was noted in 9 patients. High-risk cytogenetics were observed in 5 patients including 2 patients with del17p. All 12 subjects were evaluable for toxicity. One subject was not evaluable for response because of non-compliance. Of the eleven patients evaluable for response, the median number of cycles was 3 (range 1- 15). The median follow up was 177 days (range: 42 - 602). Three patients were treated on DL 1 (20 mg) and three on DL3 (40 mg) without incidence of DLT. At DL5 (60 mg), one patient had a DLT with grade III elevation of alanine aminotransferase; an additional three patients were enrolled at this dose level without further DLTs. One out of 12 subjects remains on treatment, 8 patients were removed from study due to disease progression, two due to adverse events (bacteremia at 60 mg, possibly related to study drug and angioedema at 40 mg, not related to study drug) and one from noncompliance. The most common toxicities were hematologic. There were 4 patients with grade 1 or 2 neutropenia on the 20 and 40 mg dose levels and 1 patient with grade 4 lymphopenia on the 40 mg dose. Except for the DLT, all non-hematologic toxicities were ≤ grade 2. Response: Although not all patients were treated at the 60 mg dose, a clinical benefit rate of 90% has been seen, with 9/10 achieving stable disease (SD). The median duration of SD among 9 patients thus far is 56 days (range: 27-401). In the five evaluable patients with high risk cytogenetics, four of them achieved a clinical benefit. Two subjects had SD lasting nearly one year or longer. In this small cohort, no association between dose and benefit was observed. Conclusion: Leflunomide is a safe and well-tolerated oral option for patients with RRMM, with a clinical benefit from single agent dosing. On the basis of our preclinical work showing synergistic inhibition of MM using leflunomide, pomalidomide, and dexamethasone, we plan clinical testing of this drug combination. Disclosures Rosenzweig: Celgene: Speakers Bureau. Krishnan:Janssen: Consultancy, Speakers Bureau; Sutro: Speakers Bureau; Onyx: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Equity Ownership, Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

A first-in-human phase I study in patients with advanced and/or refractory solid malignancies to evaluate the safety of ATOR-1015, a CTLA-4 x OX40 bispecific antibody.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3061-3061
Author(s):  
Jeffrey Yachnin ◽  
Gustav J. Ullenhag ◽  
Ana Carneiro ◽  
Dorte Nielsen ◽  
Kristoffer Staal Rohrberg ◽  
...  
Keyword(s):  
Disease Progression ◽  
Clinical Efficacy ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Single Agent ◽  
Evaluation Criteria ◽  
Vital Signs ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Solid Malignancies

3061 Background: ATOR-1015 is a human CTLA-4 x OX40 targeting IgG1 bispecific antibody developed to be a next generation CTLA-4 antibody with enhanced immune activation and tumor-directed activity for improved efficacy and reduced toxicity. Methods: The primary objective of the study is to determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) in patients with advanced solid malignancies. Safety and tolerability of ATOR-1015 are assessed by adverse events (AEs), vital signs, ECG, laboratory evaluations and physical examinations. Secondary objectives include pharmacokinetics (PK), immunogenicity and clinical efficacy. Clinical efficacy is assessed using Response Evaluation Criteria in Solid Tumors for immune-based therapeutics (iRECIST). The study is designed with single patient cohorts for doses below 100 mg followed by a modified 3+3 design (NCT03782467). Intra-patient dose escalation is allowed. ATOR-1015 is administered intravenously every other week as a single agent until confirmed progressive disease, unacceptable toxicity or withdrawal of consent. Results: From March 2019 to February 2020, 15 patients have been exposed to ATOR-1015. The median age of the patients is 52 years (range 40-72). The following cancer types have been included: colorectal cancer (n=8), uveal melanoma (n=2), pancreatic cancer (n=2), ovarian cancer (n=2), and cholangiocarcinoma (n=1). Patients received a median of 6 prior lines of therapy (range 3-16). Dose levels from 0.043 mg to 200 mg have been evaluated and declared safe. Dose escalation is ongoing, and 400 mg is under evaluation. The median time on study was 8 weeks (range 2.1-34.3). Four patients are on study and eleven patients have discontinued treatment . Reasons for discontinuation include clinical deterioration (n=7), death due to disease progression (n=2), confirmed disease progression (n=1) and investigator´s decision (n=1). Six of the 15 patients experienced drug-related AEs which were grade 2 or less. Infusion-related reactions (IRR) were reported in four patients. One of those four also had abdominal pain and mediastinal burning sensation. The IRR symptoms were predominantly rash. One patient had vitiligo, and one had rash. No dose-limiting toxicities have occurred. Preliminary PK data show dose-proportional kinetics up to 200 mg. Conclusions: The dosing of ATOR-1015 has been safe and well-tolerated up to 200 mg. Dose escalation continues and the current dose level under evaluation is 400 mg. Clinical trial information: NCT03782467 .

A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-1287 administered daily to patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3611-3611
Author(s):  
Ben George ◽  
Donald A. Richards ◽  
William Jeffery Edenfield ◽  
Steven L Warner ◽  
Lars Mouritsen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

3611 Background: TP-1287 is a an orally bioavailable phosphate prodrug of alvocidib, a cyclin dependent kinase 9 (CDK9) inhibitor. TP-1287 exhibits potent inhibition of intracellular kinases including CDK9. Inhibition of CDK9 leads to downregulation of the BCL-2 family member, MCL-1, which in turn inhibits tumor growth in preclinical animal models of prostate, breast, and lung carcinomas. Methods: This is a multicenter, Phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-1287 in patients with advanced solid tumors. Patients will be added at the maximum tolerated dose (i.e. expansion cohort) to test TP-1287 as a single agent in patients with castrate resistant prostate cancer. Results: Twenty-two patients who were enrolled between December 2018 and January 2020 received a range of doses from 1 mg QD to 11 mg BID over 7 cohorts. Data are available for 20 patients as of the data cutoff date. TP-1287 plasma PK Cmax and AUC increased in near linear fashion over cohorts 1 thru 6, reaching 80 ng/mL and 499.3 ng*h/mL in cohort 6 for Cmax and AUC, respectively. TP-1287 treatment resulted in dose-dependent reductions of phospho-RNA Pol II, consistent with CDK9 inhibition, as measured by a flow cytometric assay assessing pharmacodynamic changes in phosphorylation state in PBMCs. The most frequently observed Grade 3 AE was unrelated anemia in 2 patients. All other events of Grade 3 (9 events/7 patients) and Grade 4 (1 event/seizure with new CNS mets) were unlikely related or unrelated. Clinical benefit was seen in one sarcoma patient with PR (15+cycles), one RCC patient with SD (7+cycles) and 2 bladder cancer patients with SD (6 and 8 cycles). Conclusions: These findings suggest that TP-1287 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, refractory solid tumors and further clinical development in selected indications is warranted. Clinical trial information: NCT03298984 .

402 DRAGON: Phase 1 trial of SRK-181, a latent TGFβ1 inhibitor in combination with anti-PD-(L)1 inhibitors for patients with solid tumors unresponsive to anti-PD-(L)1 therapy alone

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A427-A427
Author(s):  
Lu Gan ◽  
Johanna Bendell
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Immune Cells ◽  
Phase 1 ◽  
Single Agent ◽  
Locally Advanced ◽  
Tumor Stroma ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Primary Resistance

BackgroundTGFβ1 is a key mediator of primary resistance to PD1 (programmed cell death protein 1) pathway blockade. SRK-181 is a high-affinity, fully humanized antibody that selectively binds to latent TGFβ1 and inhibits its activation on suppressive immune cells as well as within tumor stroma. Preclinical data demonstrated that selective inhibition of latent TGFβ1 with SRK-181 overcomes primary anti-PD-1 resistance and has an improved safety profile compared to broad inhibition of the TGFβ pathway.MethodsThe DRAGON trial is a multi-center, open-label, Phase 1, first-in-human (FIH), dose-escalation, and dose expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of SRK-181 administered by IV infusion every 3 weeks (q3w) alone and in combination with an anti-PD-(L)-1 in adult patients with locally advanced or metastatic solid tumors. The study is divided into 3 parts: Part A1, a single agent dose escalation, will determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of SRK-181 as a single agent. Part A2, a combination dose escalation, will determine the MTD or MAD of SRK-181 in combination with anti-PD-(L)1 therapy and the RP2D of the combination treatment for use in Part B. Part B, the dose expansion, will enroll parallel cohorts of patients with non-small cell lung cancer, urothelial carcinoma, melanoma, or other advanced solid tumors, to confirm the tolerability of the RP2D and to evaluate the anti-tumor activity of SRK-181 in combination with an anti-PD-(L)1 therapy. Patients in Part A2 and Part B will have previously received anti-PD-(L)1 therapy and considered non-responders to anti-PD-(L)1 therapy alone. Patients will receive SRK-181 alone or in combination with anti-PD-(L)1 until disease progression, unacceptable toxicity, or other reasons for study discontinuation. Safety, PK, PD and efficacy data will be collected and monitored throughout the study. PD effects will be assessed by measuring modulation of tumor immune cells and TGFb pathway within the tumor microenvironment.ResultsN/AConclusionsAn enrollment update will be providedTrial RegistrationNCT04291079

scholarly journals ACTR-63. PHASE I DOSE ESCALATION STUDY OF PROCASPASE ACTIVATING COMPOUND-1 (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE IN PATIENTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA OR GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi28-vi28
Author(s):  
Matthias Holdhoff ◽  
Martin Nicholas ◽  
Richard Peterson ◽  
Oana Danciu ◽  
Stefania Maraka ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Anaplastic Astrocytoma ◽  
Caspase 3 ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Dose Escalation Study ◽  
Level 1 ◽  
Level 2

Abstract BACKGROUND Procaspase activating compound -1 (PAC-1) is a small molecule that catalyzes conversion of procaspase-3 to caspase-3 which induces apoptosis in cancer cells. Glioblastoma (GBM) is among the tumors with high concentrations of procaspase-3 and low levels of caspase-3. PAC-1 crosses the blood brain barrier and has been shown to synergize with temozolomide (TMZ) in canine malignant glioma and meningioma that arise spontaneously. METHODS This is a multicenter phase 1 dose-escalation study to assess the maximum tolerated dose (MTD) of PAC-1 administered days 1–21 in combination with TMZ days 8–12 at a dose of 150 mg/m2 of each 28 day cycle in subjects with recurrent anaplastic astrocytoma (AA) or GBM. A modified Fibonacci 3 + 3 design is used with up to 4 dose levels of PAC-1 (375, 500, 625 and 750 mg/day). Neurologic toxicity, including cognitive function, is closely monitored throughout the trial. INTERIM DATA: A total of 14 subjects have been enrolled to-date. Of these, 7 at dose level 1, PAC-1 375 mg/day (6 GBM, 1 AA; median age 58y, range 25–75) and 7 at dose level 2, PAC-1 500 mg/day (5 GBM, 2 AA; median age 51y, range 35–60). Best responses to-date were 2 subjects with a partial response and 2 with stable disease. Grade 3 (hepatotoxicity) and 4 (cerebral edema) was reported as possibly related to PAC-1 in 1 patient at dose level 1. The median number of cycles received was 4 (range, 1–12+) at dose level 1 and 2 (range, 1–3) at dose level 2. Enrollment to dose level 2 has been completed and data analysis is ongoing. Updated response and toxicity as well as pharmacokinetic data will be presented.

Phase I dose-escalation, open-label study of HSP990 administered orally in adult patients with advanced solid malignancies.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2561-2561
Author(s):  
Leticia De Mattos-Arruda ◽  
Lillian L. Siu ◽  
Javier Cortes ◽  
Yann Berge ◽  
Albiruni R A Razak ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Standard Therapy ◽  
Metabolic Response ◽  
Single Agent ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Oncogenic Signaling ◽  
Open Label ◽  
Solid Malignancies

2561^ Background: NVP-HSP990 is a synthetic small molecule that potently and selectively inhibits heat-shock protein 90. HSP990 leads to degradation of client proteins, offering potential simultaneous blockade of multiple oncogenic signaling pathways. The primary objective of this Phase l first-in-man study (NCT00879905) was to determine the single-agent MTD of HSP990 administered once (qw) or twice (biw) weekly to patients (pts) with advanced solid malignancies (preselected CYP2C9 genotypes only). Secondary objectives included safety, efficacy, PK, and biomarkers. Methods: HSP990 was administered orally qw or biw in 28-day cycles. Dose escalation was guided by a Bayesian logistic regression model. The MTD was determined by assessing DLTs in Cycle 1. Eligible pts included those with histologically confirmed advanced solid tumors that had progressed on standard therapy or for whom no standard therapy exists. Results: 64 pts (median age 57 yr: 44% male; 37.5% Stage IV; WHO PS 0/1) received HSP990. 53 pts received HSP990 qw at 2.5, 5, 10, 20, 30, 50 or 60 mg; and 11 pts received HSP990 biw at 25 mg. Median duration of exposure was 8 wks; 12 pts remained on treatment for >16 wks. DLTs occurred in 7 pts: 4/22 at 50 mg qw (including G3 diarrhea, G3 QTc prolongation, G4 ALT/AST elevations); 2/5 at 60 mg qw (including G3 tremors); and 1/11 at 25 mg biw (including G2 ataxia, G2 confusion, G2 visual hallucination). The 50-mg qw dose was declared as the MTD. Further dose escalation was not possible due to neurologic toxicity. Most common reported CTCAE G3/4 AEs were diarrhea (12.5%), increased ALT/AST (11% each), anemia, or cholestasis (6% each). HSP990 had Tmax of 3 h and T½ of ~20 h. Large inter-patient variability in PK exposures was observed. For qw dosing, approximate dose-dependent HSP70 induction was observed from 5−30 mg qw, which plateaued after 20 mg qw. There were no objective responses; however, 25 pts (39%) had SD. (RECIST v1.0). No pt showed a complete metabolic response (MR; by FDG-PET) and 11 pts (17%) showed a partial MR. All pts discontinued treatment, primarily due to disease progression (84%). Conclusions: The single-agent MTD of HSP990 in pts with advanced solid tumors was 50 mg qw. SD was observed in 39% of pts. Clinical trial information: NCT00879905.

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