Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer

3001 Background: p38 MAPK regulates production of cytokines by the tumor microenvironment and its activation enables cancer cells to survive in the presence of oncogenic stress, radiation, chemotherapy, and targeted therapies. LY2228820 is a selective small-molecule inhibitor of p38 MAPK and preclinical studies demonstrate antitumor activity as a single agent and in combination with standard agents. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of LY2228820 and to characterize its pharmacokinetics and pharmacodynamics. Methods: Dose escalation was performed in a 3+3 design. LY2228820 was taken orally every 12 hours on days 1-14 of a 28-day cycle. Results: 54 patients received either capsules at 8 dose levels (10, 20, 40, 65, 90, 120, 160, and 200mg) or tablets at 5 dose levels (160, 200, 300, 420, and 560mg). For both formulations, Cmax and AUC increased in a dose-dependent manner. LY2228820 inhibited p38 MAPK induced phosphorylation of MAPKAP-K2 in peripheral blood with dose-dependent maximum inhibition from 10 to 70% across the dose range 10-200mg. The most common drug-related adverse events included fatigue, nausea, rash, constipation, vomiting, and pruritus. 1 patient (200mg) had DLT of erythema multiforme (Gr3) and 2 patients (560mg) had DLT of ataxia (Gr3) and dizziness (Gr2), respectively. Although the MTD was 420mg, the frequency of Gr1/2 adverse events (mainly rash, dizziness, and tremor) and observation of clinical activity at lower dose levels led to a recommended dose of 300mg (mean AUC0-24 = 11.7ug-hr/ml at steady state). Early clinical activity has been observed in ovary, breast, and kidney cancers. One patient with metastatic clear cell carcinoma of the kidney refractory to sorafenib, sunitinib, and temsirolimus had confirmed near partial response (29% decrease) after 8 cycles and remains on therapy. 15 patients (28%) achieved best overall response of stable disease, which in 12 patients (22%) was prolonged (≥4 cycles). Conclusions: LY2228820 demonstrates acceptable pharmacokinetics, safety, and early clinical activity as a single agent in advanced cancer. A phase II study for patients with ovary cancer is planned.

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EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

Neuro-Oncology ◽

10.1093/neuonc/noaa222.141 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii307-iii307

Author(s):

Mariko DeWire ◽

James Leach ◽

Christine Fuller ◽

Peter de Blank ◽

Trent Hummel ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Single Agent ◽

Maximum Tolerated Dose ◽

Pharmacokinetic Studies ◽

High Grade ◽

Newly Diagnosed ◽

High Grade Gliomas ◽

Grade 3 ◽

Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

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EPCT-17. A PHASE I AND SURGICAL STUDY OF RIBOCICLIB AND EVEROLIMUS IN CHILDREN WITH RECURRENT OR REFRACTORY MALIGNANT BRAIN TUMORS: PEDIATRIC BRAIN TUMOR CONSORTIUM INTERIM REPORT

Neuro-Oncology ◽

10.1093/neuonc/noaa222.139 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii307-iii307

Author(s):

Mariko DeWire ◽

Christine Fuller ◽

Olivia Campagne ◽

Tong Lin ◽

Haitao Pan ◽

...

Keyword(s):

Brain Tumors ◽

Phase I ◽

Dose Level ◽

Phase I Study ◽

Single Agent ◽

Pediatric Brain Tumor ◽

Pi3k Pathway ◽

Neurosurgical Procedures ◽

Common Grade ◽

Grade 3

Abstract Genomic aberrations in the cell cycle and PI3K pathway are commonly observed in recurrent childhood brain tumors. Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dosage (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus was determined in the Phase I study and ribociclib concentrations were characterized in plasma and tumor in children undergoing neurosurgical procedures. Following resection, eligible patients were enrolled in the Phase I study according to a rolling 6 design and received ribociclib and everolimus once daily for 21 days and 28 days, respectively. Patients undergoing surgery received ribociclib at the pediatric RP2D (350 mg/m2/day) for 7–10 days pre-operatively. Pharmacokinetic samples were collected on both cohorts and analyzed in nine patients on phase I study. Sixteen eligible patients enrolled on phase I study (median age 10.3 years; range: 3.9–20.4) and 5 patients were enrolled on the surgical cohort (median age 11.4 years; range: 7.2–17.1). Six patients enrolled at dose level 1 without dose limiting toxicities (DLT). Two of the three patients at dose level 2 experienced DLT (grade 3 hypertension and grade 4 ALT). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leucopenia. Everolimus concentrations following administration of everolimus alone were lower than those following drug combination, suggesting an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus in recurrent CNS tumors is 120 mg/m2 and 1.2 mg/ m2 daily for 21 days and 28 days, respectively.

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Phase I Study of 30-Minute Infusion of Carfilzomib As Single Agent or in Combination With Low-Dose Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2013.52.3522 ◽

2015 ◽

Vol 33 (7) ◽

pp. 732-739 ◽

Cited By ~ 58

Author(s):

Kyriakos P. Papadopoulos ◽

David S. Siegel ◽

David H. Vesole ◽

Peter Lee ◽

Steven T. Rosen ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Concentration ◽

Phase I ◽

Phase I Study ◽

Low Dose ◽

Single Agent ◽

Phase Iii ◽

Maximum Plasma ◽

Irreversible Inhibitor ◽

Refractory Multiple Myeloma

Purpose Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed. Patients and Methods Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m2, followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m2. Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk). Results Thirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m2 were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m2. Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m2 cohort). Increasing carfilzomib dosing from 20 to 56 mg/m2 resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m2 of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib. Conclusion Carfilzomib administered as a 30-minute IV infusion at 56 mg/m2 (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.

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First-In-Human Phase I Study of a Next-Generation, Oral, Transforming Growth Factor-Beta Receptor 1 Inhibitor, LY3200882 in Patients with Advanced Cancer

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-21-1504 ◽

2021 ◽

pp. clincanres.1504.2021

Author(s):

Timothy A. Yap ◽

María Vieito ◽

Capucine Baldini ◽

Juan Manuel Sepúlveda-Sánchez ◽

Shunsuke Kondo ◽

...

Keyword(s):

Growth Factor ◽

Phase I ◽

Advanced Cancer ◽

Transforming Growth Factor Beta ◽

Phase I Study ◽

Transforming Growth Factor ◽

Next Generation ◽

Beta Receptor ◽

Growth Factor Beta

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Updates in Clinical Data on FDA Fast Track Drugs for Relapsed Refractory Multiple Myeloma: A Systematic Review of Literature

Blood ◽

10.1182/blood-2019-123296 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5579-5579

Author(s):

Muhammad Abdullah Yousaf ◽

Muhaddis Ejaz Ahmad ◽

Maaz Ahmed Yusufi ◽

Asim Tameez ud din ◽

Muhammad Qudrat Ullah ◽

...

Keyword(s):

T Cell ◽

Partial Response ◽

Phase I ◽

Phase I Study ◽

Fast Track ◽

Single Agent ◽

Phase Ib ◽

D 20 ◽

Combination Regimens ◽

Good Partial Response

Introduction FDA (Food and Drug Administration) fast track program facilitates the development and accelerated review of new drugs aimed at treating life-threatening conditions and having the potential to address unmet medical needs. FDA fast track drugs (2019) for relapsed refractory MM include selective exportin-1 (XPO-1) inhibitors, first generation Selinexor / KPT-330 (S) and second generation KPT-8602, and an anti-B-cell maturation antigen (BCMA) bispecific T-cell engager (BiTE), AMG-420. The aim of our study is to analyze published literature for updates in clinical data viz efficacy and toxicity of these new agents in pts with RRMM. Methods Following PRISMA guidelines, we performed a comprehensive literature search on articles published after 2014 using Pubmed, Embase, Cochrane and Web of Science. Fifty-eight articles were identified initially and after a detailed scrutiny, we finalized 8 studies involving 299 RRMM patients and summarized the data using absolute values and percentages. Chimeric antigen receptor (CAR) T-cell therapy was excluded from our manuscript. Results Selinexor / KPT-330: A total of 6 studies (Table 1) involving 258 RRMM pts were included. In a phase Ib/II study by Bahlis et al., S was given in combination with bortezomib (V) and dexamethasone (d) to 22 pts with 4 median prior lines of therapy. The overall response rate (ORR) was 77% with complete response (CR) in 5%, partial response (PR) in 50% and very good partial response (VGPR) in 23% pts. In another phase Ib/II study by the same author, SVd was given to 42 pts with 3 median prior therapies. In 40 evaluable pts, ORR was 63% with CR in 8%, PR in 33%, and VGPR in 23%. The progression free survival (PFS) was 9 months. In a phase I/II study by Broijl et al., S (45 or 30 mg/m2) was given in combination with Vd to pts with median 3 prior treatments. Among 5 evaluable pts who received 45 mg/m2 of S, PR was observed in 80% and VGPR was observed in 40% pts. OS was 100% and 75% at 12 and 24 months respectively and PFS was 17 months. In pts who received S (30 mg/m2) with Vd, PR was observed in 67% and VGPR was observed in 17% pts. OS was 75% at 12 months and PFS was 10 months. In a phase II study by Vogl et al, 79 pts received S (80 mg) in combination with d (20 mg), both orally and twice weekly. Median prior therapies received were 7. In 78 evaluable patients, the ORR was 21% with PR in 15% and VGPR in 5%. OS and PFS were 9.3 and 2.3 months respectively. In a phase I study by Chen et al., 84 pts having received 6 median prior therapies were included. S was given either alone or in combination with d. Fourteen pts were rendered ineligible for response. ORR was 4% for pts who received single-agent S and 22% for those who received S+d. PR was observed in 4% of single-agent S pts. Among S+d pts, all responses were observed in S (45 mg/m2) plus d (20 mg) group (ORR 50%) with CR in 8% and PR in 42% pts. In a phase I study by Jakobowiak et al., 18 pts with median 3 prior therapies were included. S in combination with carfilzomib (CFZ) and d were given. Among 16 evaluable patients, PR was observed in 63% and VGPR was observed in 25% pts. On July 3, 2019, FDA granted accelerated approval to selinexor. KP-8602: In a phase I/II trial by Cornell et al., involving 6 pts, KP-8602 (5 mg PO QDx5) in combination with dexamethasone (20 mg 2QWK) was given for 28 days. they had received 6 median prior lines of therapy. PR was observed in 16% of the pts. AMG-420: In a phase I study by Topp et al., 35 pts with median 4 prior lines of therapy were included. Single-agent AMG-420 (0.2-800 µg/day) was given. CR was observed in 17% pts. The highest dose at which a CR was observed was 400 µg/day. It was also the dose at which maximum number of pts showed a CR (n=3, 9%). A partial response (PR) and a very good partial response (VGPR) was also observed in 1 patient each i.e. 3%. Conclusion Combination regimens of SVd has superior efficacy as compared to S monotherapy. Major adverse events reported with both single-agent and combination regimens are hematological i.e. thrombocytopenia, neutropenia and anemia. KP-8602 has promising efficacy in limited pts and appear to have better adverse effect profile. AMG-420 has shown promising activity and tolerability in RRMM pts at a dose of 400 µg/day with no major toxicities at this dose. The published data on these drugs is scarce, still emerging and warrants further investigation. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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