First-in-Human Phase 1 Dose Escalation Study of NPI-0052, a Novel Proteasome Inhibitor, in Patients with Lymphoma and Solid Tumor

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4939-4939 ◽  
Author(s):  
Paul A. Hamlin ◽  
Carol Aghajanian ◽  
David Hong ◽  
Anas Younes ◽  
Michael A. Palladino ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Whole Blood ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
Hematologic Malignancies ◽  
Dose Escalation Study ◽  
Elimination Half

Abstract Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities (C-L, T-L, CT-L) of the 20S proteasome. Preclinical data demonstrated activity in hematologic malignancies (myeloma, lymphoma, leukemia) and solid tumors. This Phase 1 study in patients with refractory lymphomas or solid tumors was the first-in-human study of NPI-0052. Materials and Methods: Patients were treated with NPI-0052 administered as a weekly IV injection for 3 weeks in 4-week cycles in a 3+3 design dose escalation study. The dose of NPI-0052 was escalated in 50–100% increments dependent on observed adverse events. Proteasome inhibition was assayed in whole blood and in peripheral blood mononuclear cells (PBMCs). All patients underwent plasma PK sampling. Once a Recommended Phase 2 Dose (RP2D) is identified, two groups of up to 10 patients each (lymphoma and solid tumors) will be treated at that dose. Results: 35 patients (including 5 patients with lymphoma) have been treated between 0.0125 mg/m2 to 0.55 mg/m2 for up to 12 cycles without reaching an MTD. Drug related adverse events at the highest dose level assessable (n=4) include Grade 1: diarrhea (n- 2), fatigue, muscle stiffness, hypotension and hypomagnesemia. At doses tested to date, thrombocytopenia or neuropathy have been unremarkable. SAE reported as potentially related included MRSA sepsis and post-infectious glomerulonephritis/renal failure recovering after antibiotic treatment in one patient treated at 0.1 mg/m2 and Grade 4 neutropenia recovering after 3 days in one patient treated at 0.112 mg/m2. Preliminary PK data indicate an elimination half life of approximately 3–13 minutes, with clearance at 11.7 ± 7.4 mL/min and Vz of 44–99L. Proteasome inhibition in whole blood demonstrate dose dependency for CT-L inhibition (at 0.55 mg/m2), mean D1 and D15 inhibition in whole blood equaled 65 and 90%, respectively. Using PBMCs (cells that can regenerate proteasomes), similar CT-L inhibition was also observed on D1 and D15. Inhibition returned to baseline within one week of each dose in PBMC, whereas significant inhibition remained throughout the cycle in whole blood. No responses have been confirmed; stable disease (>3 months) was observed in patients with cervical carcinoma (11 months; time to progression on the prior treatment regimen was 3 months), colorectal, hepatocellular (6 months), adenoid cystic (4 and 5 months), melanoma (4 months), granulosis cell and ovarian (3+ months). The patient with cervical carcinoma, underwent four dose escalations (from 0.025 to 0.168 mg/m2) with increased proteasome inhibition observed at each higher dose assessed (from 24% to 64%). Preliminary PK data indicate an elimination half life of approximately 3–13 minutes, with clearance at 11.7 ± 7.4 mL/min and Vz of 44–99L. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the range of proteasome inhibition produced by therapeutic doses of the approved proteasome inhibitor bortezomib without resulting in the toxicity profile seen with bortezomib treatment. These data have supported additional studies being initiated in hematologic malignancies and solid tumors, including combination studies with other targeted agents.

Phase 1 Clinical Trial of a Novel Proteasome Inhibitor (NPI-0052) in Patients with Lymphomas and Solid Tumors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4504-4504
Author(s):  
Razelle Kurzrock ◽  
Paul Hamlin ◽  
Anas Younes ◽  
David Hong ◽  
Michael Gordon ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
Pharmacokinetic Data ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Elimination Half

Abstract NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities (C-L, T-L, CT-L) of the 20S proteasome. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with activity in multiple myeloma, lymphoma, leukemia and solid tumor models. Phase 1 dose escalation studies are ongoing in patients with myeloma, lymphomas and solid tumors. Data from the Phase 1 study in patients with lymphomas or solid tumors are presented herein to examine the endpoints of pharmacodynamics (proteasome inhibition), pharmacokinetics and safety at doses below the MTD. Patients in this study were treated with NPI-0052 administered as a weekly IV bolus, for 3 weeks in 4-week cycles. The dose of NPI-0052 was escalated in cohorts of 3 patients dependent on observed adverse events utilizing a 3+3 design. In addition to weekly safety monitoring, proteasome inhibition and pharmacokinetics were assayed after the 1st and 3rd dose and with intrapatient dose escalations. Sixteen patients have been treated at doses ranging from 0.0125 mg/m2 to 0.112 mg/m2 for up to 7 cycles without reaching an MTD. Although, one SAE of MRSA sepsis and renal failure was reported at a dose of 0.1 mg/m2, drug related adverse events have not been reported at 0.112 mg/m2. Proteasome inhibition in whole blood has been assayed from 0.0125 mg/m2 through 0.075 mg/m2, with results ranging from no inhibition to 63% inhibition of CT-L activity and indication of a correlation of inhibition with dose, inclusive of intrapatient dose increases. Preliminary pharmacokinetic data demonstrate a rapid elimination half-life (estimated to be 3–4 minutes) with clearance between 8–21 mL/min and Vz of 44–99L. No responses have been confirmed, however, 4 patients have had stable disease for 4 or more months, including patients with hepatocellular carcinoma (6 months), adenoid cystic carcinoma (4 months and 4 months), and cervical carcinoma [7 months with investigator reported complete resolution of target (lymph node) lesion(s) to palpation]. These data suggest that NPI-0052 is affecting parameters relevant to pharmacodynamics, pharmacokinetics and potentially clinical benefit at doses below the MTD. Dose escalation continues to define a recommended phase 2 dose and further investigate the relevance of these outcomes in larger Recommended Phase 2 Dose Cohorts.

Phase 1 Clinical Trial of NPI-0052, a Novel Proteasome Inhibitor in Patients with Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2770-2770 ◽  
Author(s):  
Paul Richardson ◽  
Craig C. Hofmeister ◽  
Todd M. Zimmerman ◽  
Asher Alban Chanan-Khan ◽  
Matthew A. Spear ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
Significant Activity ◽  
Potential Clinical Benefit

Abstract Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities (C-L, T-L, CT-L) of the 20S proteasome. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with significant activity in hematologic and solid tumor malignancies including multiple myeloma (MM) resistant to bortezomib and other agents (Chauhan et al, Blood 2006). Studies have therefore been initiated in patients with multiple myeloma, lymphoma, leukemia and solid tumors. Materials and Methods: This Phase 1 dose escalation study evaluated NPI-0052 monotherapy in patients with relapsed and relapsed/refractory MM, including those that have received bortezomib and/or lenalidomide. Patients were assessed for safety, pharmacodynamics (including ex vivo proteasome inhibition), plasma pharmacokinetics (PK), and clinical activity (with response assessed by modified EBMT criteria). Patients were treated with NPI-0052 administered as a weekly IV injection on Days 1, 8 and 15 every 4 weeks with concomitant hydration. The dose of NPI-0052 was escalated in cohorts of 3 patients dependent on observed adverse events utilizing a 3+3 design. Proteasome inhibition and PK were assayed after the 1st and 3rd dose and upon any intra-patient dose escalation. Proteasome inhibition was also assessed in CD138 positive cells isolated from bone marrow aspirates obtained at baseline and after the 3rd dose in a subset of patients. Preliminary Results: To date, 10 patients have been treated at doses ranging from 0.025 mg/m2 to 0.075 mg/m2 without reaching an MTD. One patient experienced reversible elevation in serum creatinine that responded to drug cessation and steroids; this event may have been related to progression of his underlying light chain nephropathy (as interval worsening of renal function was noted prior to enrollment). Drug-related adverse events have been otherwise unremarkable at all dose levels tested. PK data demonstrate a rapid elimination half life (estimated to be 3–4 minutes) with clearance between 8–21 mL/min and Vz of 44–99L; no change in PK has been observed comparing the 1st and 3rd injection. Proteasome inhibition in whole blood suggests drug-dependent CT-L inhibition, with inhibition up to 28% observed (inhibition up to 100% at doses of up to 0.7 mg/m2 has been observed in other clinical trials with NPI-0052 without producing the profile of toxicity reported with standard doses of bortezomib). Whilst no responses have been confirmed, two patients with relapse/refractory MM remained on study for over 6 months and one year, respectively, with stable disease and no significant toxicity. Importantly, no peripheral neuropathy or myelosuppression has been seen in 41 treatment cycles in patients to date. Conclusions: In patients with relapsed and relapsed, refractory MM, NPI-0052 affects parameters relevant to pharmacodynamics, PK and demonstrated potential clinical benefit at doses well below the MTD anticipated from Phase 1 clinical trials with NPI-0052 in lymphoma and solid tumors. Drug administration to date has been well tolerated. Dose escalation continues to define DLT and MTD, and to recommend a phase 2 dose for further study in patients with advanced MM.

scholarly journals A Phase 1 Dose Escalation Study of the Safety and Pharmacokinetics of the Novel Proteasome Inhibitor Carfilzomib (PR-171) in Patients with Hematologic Malignancies

2009 ◽  
Vol 15 (22) ◽  
pp. 7085-7091 ◽  
Author(s):  
Owen A. O'Connor ◽  
A. Keith Stewart ◽  
Marcy Vallone ◽  
Christopher J. Molineaux ◽  
Lori A. Kunkel ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
The Novel ◽  
Dose Escalation Study

A first-in-human phase dose-escalation study of YH002, a recombinant humanized agonistic anti-OX40 IgG1 monoclonal antibody, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14501-e14501
Author(s):  
Vinod Ganju ◽  
Adam Cooper ◽  
Kate Wilkinson ◽  
John J. Park
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Cancer Breast ◽  
Dose Levels

e14501 Background: YH002 is a recombinant humanized IgG1 antibody that targets the human OX40 receptor. Preclinical studies have demonstrated the specificity, potency, and anti-cancer efficacy of YH002 in a comprehensive panel. The totality of nonclinical data supports progression of YH002 into clinical studies in adult patients (pts) with advanced solid tumors. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced or metastatic refractory solid tumors received YH002 as single agent by IV administration at 0.01 to12.0 mg/kg dose levels every 21 days (Q3W), to evaluate the safety, tolerability and preliminary efficacy. An accelerated titration dose escalation design followed by a traditional 3+3 dose algorithm were utilized to assess dose-limiting toxicity (DLT) and identify MTD and/or RP2D. Tumor assessments were performed per RECIST v1.1 every 9 weeks. Results: By December 31 2020, six patients were enrolled and treated at escalating dose levels of 0.01 (n=1), 0.03 (n=1), 0.1 (n=1) and 0.3mg/kg (n=3), with tumor types including colon cancer, thymic cancer, prostate cancer, colorectal cancer, breast cancer and bladder cancer. Median treatment duration was 10.2 weeks (range 2 – 18). The median age of patients was 67 years old (range 47-78). These patients had progressed after a median of 2 prior lines of available standard therapy. As of data cutoff, no dose limiting toxicities (DLTs), no Grade (G) 3 or above adverse events (AE) or AEs leading to treatment discontinuation were reported. Drug-related adverse events (AEs) were all G1/2 events and occurred in 4 patients, including 8 G1 AEs (pneumonitis, rash, pruritus, arthralgia, myalgia, fatigue, lethargy, rash pruritic) and 3 G2 AEs (1 pneumonitis and 2 fatigue). Out of 5 patients having tumor assessment by RECIST, one pt with Thymic SCC at 0.3 mg/kg had best response of stable disease at week 9, one pt with prostate cancer at 0.1 mg/kg experienced Non-CR/Non-PD, and rest of 3 pts experienced progressive disease. Conclusions: These preliminary results demonstrate that YH002 was safe and tolerable up to 0.3mg/kg. Updated safety and antitumor activity will be presented. Clinical trial information: NCT04353102.

A first-in-human phase I dose escalation of YH001, an anti-CTLA-4 monoclonal antibody (mAb) in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2577-2577
Author(s):  
Vinod Ganju ◽  
Adam Cooper ◽  
Bo Gao ◽  
Kate Wilkinson
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Gastroesophageal Junction Cancer ◽  
Anti Cancer ◽  
Ongoing Phase

2577 Background: YH001 is a humanized anti -hCTLA-4 IgG1 mAb that relieves CTLA-4-mediated immunosuppression, and thereby enhances the T-cell-mediated antitumor immune response. Pre-clinical data have shown potent anti-cancer activity when combined with anti-PD-1 mAb. Methods: This is an ongoing phase 1 dose-escalation study. Patients (pts) with advanced solid tumors received YH001 by IV administration at 0.05 to 6.0 mg/kg for 1 cycle (21 days) then in combination with Toripalimab (anti-PD-1 mAb) at 240 mg Q3W for 4 cycles. An accelerated titration method followed by the standard “3+3” design was utilized to evaluate safety, tolerability and preliminary efficacy. Results: As of 31-Dec-2020 data cut-off, 10 pts were enrolled and treated at 0.05 mg/kg (n = 2), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3) and 1 mg/kg (n = 2). The median age was 62 years (range 46-74). Baseline ECOG scores were 0 (n = 8), 1(n = 2) with all pts progressed after a median of 2 prior lines of available standard therapy (range 1-4) including 1 pt progressed after immunotherapy of pembrolizumab. There were no dose limiting toxicities (DLT) observed. No severe adverse events (SAEs), Grade (G) 3 or above adverse events (AEs) and AEs leading to treatment discontinuation were reported. Twelve drug related AEs were all G1/2 events including 2 G2 AEs (1 rash maculopapular at 0.05mg/kg, 1 hypothyroidism at 0.1mg/kg), 10 G1 AEs (1 hypotension, 1 dry skin, 1 pruritus at 0.05mg/kg; 1 rash, 1 rash macular, 1 hyperthyroidism, 2 rash pruritus at 0.1mg/kg, 2 fatigues at 0.3mg/kg). Among 7 patients having imaging tumor assessment by RECIST v1.1, there were 4 SD, including 1 at 0.05 mg/kg with tongue carcinoma at week 8 assessment, 1 at 0.1 mg/kg with nasopharyngeal carcinoma at week 8 and 15 assessment, 2 at 0.3 mg/kg with gastroesophageal junction cancer and uterus leiomyosarcoma at week 8. Conclusions: YH001 combined with Toripalimab is safe and tolerable up to 1 mg/kg dose level. Updated safety and preliminary efficacy data will be presented. Clinical trial information: NCT04481009.

A Phase 1b Dose-Escalation Study of Split-Dose Oprozomib (ONX0912) in Patients with Hematologic Malignancies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 203-203 ◽  
Author(s):  
Michael R. Savona ◽  
Jesus G. Berdeja ◽  
Susan J Lee ◽  
Hansen Wong ◽  
Ju RueyJiuan Lee ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
Dose Schedule ◽  
Hematologic Malignancies ◽  
Advisory Board ◽  
Dose Escalation Study ◽  
Split Dose ◽  
Dose Dependent

Abstract Abstract 203 Background: Oprozomib (OPZ, formerly ONX 0912), a structural analog of carfilzomib (CFZ), is an orally bioavailable, next-generation proteasome inhibitor being evaluated in hematologic malignancies and solid tumors. Similar to CFZ, OPZ is a potent, selective, and irreversible proteasome inhibitor. In an earlier dose-escalation study of once-daily (QD) OPZ in patients with advanced refractory solid tumors, the maximum tolerated dose (MTD) was 150 mg QD, leading to exploration of a split-dose schedule with the drug administered twice daily (BID). The present phase 1 study (NCT01416428) is evaluating OPZ administered using the split-dose schedule in patients with hematologic malignancies. Methods: This is an ongoing, phase 1b, open-label, dose-escalation study of OPZ in patients with hematologic malignancies. The primary objectives are to evaluate safety and tolerability and to determine the MTD. Secondary objectives of the study include pharmacokinetic and pharmacodynamic analyses. OPZ is administered PO on days 1–5 of a 14-day cycle using a standard 3 + 3 dose-escalation scheme. Treatment was initiated at 120 mg (60 mg BID), with an interval of 4–6 h between doses, with escalation in 30-mg increments in successive cohorts until MTD is determined. Tumor response is assessed by investigator. Results: As of June 15, 2012, 9 patients have been enrolled in the study, 3 in each of the 120-mg, 150-mg, and 180-mg dosing cohorts. No dose-limiting toxicities have been observed. Enrollment is ongoing at 210 mg/day. The median age of all patients is 67 years (range 53−81) and prior therapies included a median of 4 chemotherapy regimens (range 2−8). Patients have received a median of 5 cycles of treatment with OPZ, including 4 patients who have received ≥6 cycles. Dose reduction was required by only 1 patient in the 180-mg (90 mg BID) group for Grade 3 diarrhea and abdominal pain. Gastrointestinal (GI) AEs predominantly of Grade 1/2 in severity were the most common, with diarrhea and nausea each occurring in 7 patients, and vomiting occurring in 6 patients. The majority of GI AEs improved or resolved with concomitant medications. Thrombocytopenia was the only Grade 3/4 AE reported in more than 1 patient, occurring in 3 patients (1 at each dose level). Notably, no events of peripheral neuropathy were noted in patients in the first 3 dosing cohorts. AEs led to discontinuation in 2 patients at the 180-mg dose level, and no deaths have been reported. OPZ showed dose-dependent exposure across the 120- to 180-mg dose levels. Patients receiving split dosing had similar total exposure and lower Cmax than patients receiving QD dosing of the same total daily dose, although there was high inter-patient variability. Dose-dependent proteasome inhibition was observed in whole blood and increased from the first to the second of the split daily doses. Proteasome inhibition levels were similar to those achieved with single-dose equivalents and were >80% at the 180-mg dose level. Eight of 9 patients are evaluable for efficacy. There was preliminary evidence of anti-tumor activity of ≥SD across all doses, including 1 patient with chronic lymphocytic leukemia who attained a PR after prior exposure to 3 lines of therapy, and 1 PR and 1 MR in patients with multiple myeloma. Conclusions: Oral OPZ was generally well tolerated using a split-dose schedule in this phase 1 trial in patients with hematologic malignancies. AEs were generally mild and manageable. An MTD has not been reached at cumulative doses up to 180 mg/d (90 mg BID). Dose-dependent proteasome inhibition was observed, with >80% inhibition at the highest dose tested. OPZ also demonstrated encouraging clinical activity across the first 3 dose levels in heavily pretreated patients. Dose escalation will continue until the MTD is reached, with planned phase 2 expansion at the MTD in patients with hematologic malignancies. Disclosures: Off Label Use: Oprozomib is in Phase 1 clinical trials for hematologic malignancies and is not approved by the FDA for any use. Lee:Onyx Pharmaceuticals: Employment. Wong:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Gillenwater:Onyx Pharmaceuticals: Employment. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau.

PF-06939999, a potent and selective PRMT5 inhibitor, in patients with advanced or metastatic solid tumors: A phase 1 dose escalation study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3019-3019
Author(s):  
Jordi Rodon Ahnert ◽  
Cesar Augusto Perez ◽  
Kit Man Wong ◽  
Michael L. Maitland ◽  
Frank Tsai ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Urothelial Cancer ◽  
Phase 1 ◽  
Dose Range ◽  
Median Number ◽  
Splicing Factor ◽  
Dose Escalation Study ◽  
Study Objective ◽  
Dose Dependent

3019 Background: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates known to be dysregulated in cancer, including components of the spliceosome machinery. PF-06939999 is a selective small-molecule inhibitor of PRMT5. Here we report the safety, PK, PD, and preliminary activity of PF-06939999 in patients (pts) with selected advanced/metastatic solid tumors. Methods: This phase 1 dose escalation trial (NCT03854227) enrolled pts with solid tumor types marked by potential frequent splicing factor mutations, including advanced/metastatic endometrial cancer, head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), urothelial cancer, cervical cancer, or esophageal cancer. PF-06939999 monotherapy was continuously administered orally QD or BID in 28-day cycles. A Bayesian Logistic Regression Model was used to inform dose level decisions. Primary objectives were to assess dose limiting toxicities (DLTs), AEs and laboratory abnormalities. Tumor response was assessed using RECIST v1.1. PK and PD were assessed by determining PF-06939999 plasma concentration after dosing and changes in plasma levels of symmetric di-methyl arginine (SDMA), the product of PRMT5 enzymatic activity. Results: 28 pts received PF-06939999 at doses from 0.5-12 mg daily (QD or BID) during dose escalation. Median number of cycles was 2 (range, 1-13). Most were female (54%) with a median age of 61.5 (range, 32-84) y. Median number of prior therapies was 4. Overall, 4/24 (17%) pts reported DLTs: thrombocytopenia (n=2, 6 mg BID); anemia (n=1, 8 mg QD); and neutropenia (n=1, 6 mg QD). Treatment-related AEs occurred in 24 (86%) pts. Most common (≥20%) treatment-related AEs across all cycles were anemia (43%), thrombocytopenia (32%), dysgeusia, fatigue and nausea (29% each). Grade ≥3 treatment-related AEs included anemia (25%), thrombocytopenia (21%), fatigue, neutropenia and lymphocyte count decreased (4% each). One pt (6mg BID) had Grade 4 treatment-related thrombocytopenia. All cytopenias were dose-dependent and reversible with dose modification. No pts discontinued treatment for treatment-related toxicity. There were no treatment-related deaths. Exposure to PF-06939999 increased with doses in the dose range tested. Plasma SDMA was reduced at steady state (58.4-87.5%), indicating robust PD target inhibition. Two pts had confirmed partial response (HNSCC and NSCLC). 6 mg QD was identified as the recommended monotherapy dose for expansion. Conclusions: PF-06939999 showed dose-dependent and manageable toxicities in this phase 1 dose escalation study. Objective tumor responses were observed in pts with HNSCC and NSCLC. Analysis of archival tissue for the presence of splicing factor mutations and other potential predictive biomarkers is ongoing. Enrollment to part 2 dose expansion is ongoing in pts with NSCLC, HNSCC and urothelial cancer. Clinical trial information: NCT03854227.

Phase 1, open-label, dose-escalation study of sorafenib in combination with eribulin in patients with advanced, metastatic, or refractory solid tumors

2018 ◽  
Vol 81 (4) ◽  
pp. 727-737 ◽  
Author(s):  
Frederik Marmé ◽  
Carlos Gomez-Roca ◽  
Kristina Graudenz ◽  
Funan Huang ◽  
John Lettieri ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

Phase I open-label, dose escalation of YH003, an anti-CD40 monoclonal antibody in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2580-2580
Author(s):  
Jermaine Coward ◽  
Afaf Abed ◽  
Adnan Nagrial ◽  
Ben Markman
Keyword(s):  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Febrile Episodes ◽  
Antigen Presenting

2580 Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles in an accelerated “3+3” design. The safety, tolerability and preliminary efficacy data will be analyzed. Results: As of 31 Dec 2020 data cutoff, 9 patients (pts) were enrolled and treated at 0.03 mg/kg (n = 3), 0.1mg/kg (n = 3), and 0.3mg/kg (n = 3). The median age was 63 years (range 33-68). Baseline ECOG scores were 0 (7 pts) and 1 (2 pts) with a median of 2 prior lines therapy (range 1-7). 5 pts had received prior immunotherapy (PD-1/PD-L1 or PD-1+CTLA-4). As of data cutoff, no dose limiting toxicities (DLT) were observed. No Serious Adverse Event (SAE) or AEs leading to treatment discontinuation were reported. Four drug related AEs were reported including one Grade 1 (G1) choroidal thickening (related to YH003) at 0.03 mg/kg, one G1 fatigue (related to YH003) at 0.1 mg/kg, two G1 febrile episodes (one related to YH003 and the other related to combination treatment) at 0.3 mg/kg. Among 5 patients assessable for response, there were 2 SD (one with anti-PDL1 refractory Merkel cell carcinoma at 0.03 mg/kg and one with anti-PD1 refractory NSCLC at 0.1 mg/kg) and 1 PR with anti-PD1/anti-CTLA4 refractory ocular melanoma at 0.1 mg/kg. Conclusions: YH003 was well tolerated up to 0.3 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.

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