Phase I Study of a Novel Oral JAK-2 Inhibitor SB1518 In Patients with Relapsed Lymphoma: Evidence of Clinical and Biologic Activity In Multiple Lymphoma Subtypes.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2830-2830 ◽  
Author(s):  
Anas Younes ◽  
Michelle A. Fanale ◽  
Peter McLaughlin ◽  
Amanda Copeland ◽  
Joy Zhu ◽  
...  
Keyword(s):  
Phase I ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Phase I Study ◽  
Prior Treatment ◽  
Once Daily ◽  
Treatment Regimens ◽  
Relapsed Lymphoma ◽  
Dose Levels ◽  
Stat Pathway

Abstract Abstract 2830 Introduction: The Janus kinase 2 (JAK2) signal transducers and activators of transcription (STAT) pathway plays an important role in the proliferation and pathogenesis of hematological malignancies. In vitro inhibition of JAK2 results in antiproliferative activity in a variety of lymphoma cell lines. We have completed dose-escalation in a Phase-I study of the novel small molecule JAK2 inhibitor SB1518 in patients with relapsed Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL). Patients and Methods: The primary objectives were to examine the safety and efficacy of SB1518 in this patient population. Patients were eligible if they had relapsed or refractory HL or NHL of any type except Burkitt's, any number of prior treatment regimens as well as adequate organ function and performance status. They were excluded if they had HIV infection or CNS lymphoma. Cohorts of 3–6 patients received escalating dose levels of SB1518 orally once daily for 28-day cycles. Response was first evaluated after 8 weeks (2 cycles) of therapy. Results: Thirty patients have been enrolled (14 HL, 3 mantle cell [MCL], 8 follicular [FL], 4 diffuse large B-cell [DLBCL], 1 small lymphocytic [SLL]). Patients have been treated orally once daily at 5 dose levels, 100 mg (n=3), 200 mg (n=7), 300 mg (n=6), 400 mg (n=7) and 600 mg (n=7). Twenty of 30 patients were male and 10 were female. 28 have received SB1518 of which twenty-six are evaluable for tumor response and all 28 are evaluable for safety. The median number of prior treatment regimens was 5.5 (range 2–15), Prior treatment included an autologous transplant in 12 patients and an allogeneic stem cell transplant in 2. Treatment was well tolerated, with the most common Grade 1–2 toxicities (≥10% in frequency) being: constipation 43% (n=12), diarrhea 43% (n=12), pyrexia 32% (n=9), nausea 29% (n=8), cough and fatigue 21% (n=6), decreased appetite 18% (n=5) and anemia, anorexia, chills, dyspnea, headache, peripheral edema, peripheral neuropathy 11% (n=3). Grade 3–4 toxicities included: neutropenia 7% (n=2), abdominal distension, anemia, bacteremia, cellulitis, cerebral vascular accident, dyspnea, fatigue, hyperbilirubinemia, hypotension, lymphopenia, musculoskeletal pain, peripheral edema, pneumonia, pulmonary embolism, pyelonephritis, retroperitoneal hemorrhage and thrombocytopenia 4% (n=1). Dose escalation has been halted at 600 mg without identification of the MTD and enrollment continues in an expanded 600 mg cohort to confirm the recommended Phase II dose. There were no CRs, 3 patients had PRs (2 MCL, 1 FL at 300, 400, 600 mg), and 13 patients had SD (7 FL, 5 HL, 1 SLL), with the majority of responses sustained for >2 months. Of the patients with SD 7/13 had reduction in tumor mass of 4–46%. Serial plasma samples were collected for PK analysis. Pharmacologically active concentrations were achieved at the lowest dose level (100 mg). Dose related increases in AUC were seen on C1D1 and C1D15 up to 400mg. The terminal half-life was 1–3 days, and mean Tmax ranged between 5–9 hours. The effect of drug treatment on pJAK2, pSTAT3, and pSTAT5 was examined in PBMCs and whole blood before and after the first dose of SB1518. SB1518 inhibited the JAK/STAT pathway as early as 4 hrs after the first dose at all dose levels. Plasma was collected at each cycle to assess changes in cytokines, chemokines and growth factors. Data show marked reductions in inflammatory cytokines such as IFNalpha, as well as in PDGFalpha and beta, VEGF and RANTES in >50% of patients with samples tested (SB1518 dose levels of 100, 200, and 300 mg). Samples from higher dose levels are being tested and results will be correlated to response. Efficacy and biomarker data confirm the activity of SB1518 in multiple lymphoma subtypes and show the safety of chronic administration at doses up to 600 mg daily. Collectively these data suggest that targeting the JAK2 pathway has therapeutic value in patients with relapsed lymphoma. A Phase II trial of SB1518 in selected lymphomas is being initiated. Disclosures: Zhu: S*BIO: Employment.

Phase-I Study of the Novel Oral JAK-2 Inhibitor SB1518 in Patients with Relapsed Lymphoma: Evidence of Clinical and Biologic Activity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 588-588 ◽  
Author(s):  
Anas Younes ◽  
Michelle Fanale ◽  
Peter McLaughlin ◽  
Amanda R Copeland ◽  
Silvana de Castro Faria ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase I Study ◽  
Tumor Response ◽  
Prior Treatment ◽  
The Novel ◽  
Treatment Regimens ◽  
Relapsed Lymphoma ◽  
Stat Pathway

Abstract Abstract 588 The Janus kinase 2 (JAK2)/ signal transducers and activators of transcription (STAT) pathway plays an important role in the proliferation and pathogenesis of hematological malignancies. Somatic activating point mutations in the JAK2 gene has been reported in most myeloproliferative disorders (MPDs), but are rarely described in Hodgkin (HL) and non-Hodgkin lymphomas (NHL). JAK2 activation has been reported to be associated with mutation of the Suppressor of Cytokine Signaling (SOCS)-1 gene in HL and primary mediastinal large cell NHL, and in vitro inhibition of JAK2 demonstrated antiproliferative activity in a variety of lymphoma cell lines. With this background, we initiated a Phase-I study of the novel JAK2 small molecule inhibitor SB1518 in patients with relapsed HL and NHL. Patients and Methods: The primary objectives were to examine the safety and efficacy of SB1518 in this patient population. Patients were eligible if they had relapsed or refractory HL or NHL of any type (except Burkitt's), regardless of the number of prior treatment regimens. They were required to have adequate organ functions and performance status. They were excluded if they had HIV infection or CNS lymphoma. Patients were treated at 4 dose levels (100 mg, 200 mg, 300 mg, and 400 mg) orally daily without interruption. After 8 weeks of therapy, they were evaluated for tumor response. Results: To date, 18 patients are enrolled, of whom, 17 received SB1518. Fifteen of the 17 patients are evaluable for tumor response and safety. The median number of prior treatment regimens was 5 (range 2-8), six patients previously treated with autologous and two with allogeneic stem cell transplant. Treatment was very well tolerated, most common Grade 1-2 toxicities: diarrhea 40% (n=6), constipation 40% (n=6), nausea 27% (n=4), appetite decrease 27% (n=4), fatigue 27% (n=4), Grade 3-4 toxicities: neutropenia 13% (n=2), fatigue 7% (n=1), and cerebrovascular accident 7% (n=1). Dose escalation continues as the MTD has not been reached. Three patients at the 300 mg dose level demonstrated disease response with reductions in the tumor measurements by 24% (follicular lymphoma), 46% (small lymphocytic lymphoma), and 64% (mantle cell lymphoma), all remain on therapy with ongoing responses. Overall, 11 patients (73%) had stable disease. Serial plasma samples were collected for PK analysis. Pharmacologically active concentrations were achieved at the lowest dose level (100 mg), with a terminal half-life of 1-2 days, and a mean Tmax ranging between 5-11 hours. The effect of drug treatment on pJAK2, pSTAT3, and pSTAT5 was examined in PBMCs and whole blood before and after the first dose of SB1518. Preliminary analysis demonstrated that SB1518 inhibited JAK/STAT pathway as early as 4 hrs. Collectively, these data demonstrate the safety of chronic administration of the oral JAK2 inhibitor SB1518. As the MTD has not been reached, dose escalation continues. Ongoing clinical responses observed in a variety of lymphoma subtypes suggest that targeting JAK2 pathway may have therapeutic value in patients with relapsed lymphoma. Disclosures: Younes: SBIO: Research Funding. Off Label Use: SB1518 is an investigational drug. Wood:SBio: Employment. Ethirajulu:SBio: Employment. Zhu:S*BIO PTE LTD: Employment.

scholarly journals Switch Control Inhibition of KIT and PDGFRA in Patients With Advanced Gastrointestinal Stromal Tumor: A Phase I Study of Ripretinib

2020 ◽  
Vol 38 (28) ◽  
pp. 3294-3303 ◽  
Author(s):  
Filip Janku ◽  
Albiruni R. Abdul Razak ◽  
Ping Chi ◽  
Michael C. Heinrich ◽  
Margaret von Mehren ◽  
...  
Keyword(s):  
Phase I ◽  
Gastrointestinal Stromal Tumor ◽  
Dose Escalation ◽  
Phase I Study ◽  
Stromal Tumor ◽  
Second Line ◽  
Once Daily ◽  
Switch Control ◽  
Wide Range ◽  
Advanced Gist

PURPOSE In advanced gastrointestinal stromal tumor (GIST), there is an unmet need for therapies that target both primary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins. Ripretinib is a novel switch-control kinase inhibitor designed to inhibit a wide range of KIT and PDGFRA mutations. PATIENTS AND METHODS This first-in-human, to our knowledge, phase I study of ripretinib (ClinicalTrials.gov identifier: NCT02571036) included a dose-escalation phase and subsequent expansion phase at the recommended phase II dose (RP2D). Eligible patients included those with advanced GIST, intolerant to or experienced progression on ≥ 1 line of systemic therapy, and other advanced malignancies. Safety, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and preliminary antitumor activity were evaluated. RESULTS At data cutoff (August 31, 2019), 258 patients (n = 184 GIST) were enrolled, with 68 patients in the dose-escalation phase. Three DLTs were reported: grade 3 lipase increase (n = 2; 100 mg and 200 mg twice a day) and grade 4 increased creatine phosphokinase (n = 1; 150 mg once daily). MTD was not reached (maximum dose evaluated, 200 mg twice a day); 150 mg once daily was established as the RP2D. The most frequent (> 30%) treatment-emergent adverse events in patients with GIST receiving ripretinib 150 mg once daily (n = 142) were alopecia (n = 88 [62.0%]), fatigue (n = 78 [54.9%]), myalgia (n = 69 [48.6%]), nausea (n = 65 [45.8%]), palmar-plantar erythrodysesthesia (n = 62 [43.7%]), constipation (n = 56 [39.4%]), decreased appetite (n = 48 [33.8%]), and diarrhea (n = 47 [33.1%]). Objective response rate (confirmed) of 11.3% (n = 16/142) ranging from 7.2% (n = 6/83; fourth line or greater) to 19.4% (n = 6/31; second line) and median progression-free survival ranging from 5.5 months (fourth line or greater) to 10.7 months (second line), on the basis of investigator assessment, were observed. CONCLUSION Ripretinib is a well-tolerated, novel inhibitor of KIT and PDGFRA mutant kinases with promising activity in patients with refractory advanced GIST.

Phase I study of bortezomib and oxaliplatin (BOX) in solid tumors: Improved neurotoxicity (NT) profile with lower bortezomib (B) dose

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12007-12007
Author(s):  
R. A. Kosloff ◽  
J. Wright ◽  
P. Ivy ◽  
J. Escalon ◽  
B. Norwood ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Major Contributor ◽  
Organ Function ◽  
Dose Escalation Study ◽  
Adequate Organ Function ◽  
Dose Levels ◽  
Platinum Agents

12007 Background: B inhibits proteasome function and may be synergistic in causing apoptotic death with platinum agents. We were interested in combining B with OX but concerned with dose limiting (DL) NT based on our prior B phase I study [Hamilton et al., JCO 2005]: therefore this Phase I dose-escalation study (alternating increases of B and OX) focusing on NT was planned. Methods: Patients (pts) with metastatic solid tumors, PS 0–2, platinum or taxane naive, no peripheral neuropathy and adequate organ function, received B (D1, 4, 15, 18) and OX (D1, 15) every 28 days in a dose escalation design (see table ). Baseline and monthly assessments were performed by an independent neurologist. Results: 27 (18 gastrointestinal, 3 melanoma, 3 ovarian, 3 others) were accrued; pt characteristics: 14 male/13 female; median age 55 years (range 35–75); 2 median cycles (range 1–10). NT was not DL because it did not occur within the first cycle. Late and limiting NT was observed in levels 2–5 after 2–9 cycles, but serial neurologic evaluations showed reversible NT. With an amended new dose level to lower B to 1.0 mg/m2 (level 6) to avoid late NT, NT was not observed. Of 22 evaluable pts, there were 3 partial responses (ampullary, GE junction, biliary), 6 stable disease, and 13 disease progression by RECIST criteria. Conclusions: biweekly BOX is tolerable at B 1.0 mg/m2 and OX 85 mg/m2 with no DL NT. Additional observations on late NT are ongoing. This suggests B is a major contributor to NT observed in dose levels 2–5 and may potentiate the effects of OX. [Table: see text] [Table: see text]

scholarly journals Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1869-1869 ◽  
Author(s):  
Noopur S. Raje ◽  
Andrzej Jakubowiak ◽  
Cristina Gasparetto ◽  
Robert F. Cornell ◽  
Heike I. Krupka ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase I Study ◽  
Employment Equity ◽  
Advisory Committees ◽  
Best Response ◽  
Equity Ownership ◽  
Dose Levels

Introduction: PF-06863135 (PF-3135) is a bispecific, humanized, monoclonal antibody (mAb) consisting of BCMA- and CD3-targeting arms paired on an IgG2a backbone by hinge-mutation technology. PF-3135 binds BCMA+ myeloma cells and CD3+ T cells with affinities of 20 pM and ~40 nM, respectively (Panowski et al. Blood 2016). We report here findings from the dose-escalation portion of an ongoing, multi-center, open-label, phase I study (NCT03269136) of PF-3135 in patients with RRMM. Methods: Adult patients (≥18 years of age) with RRMM, previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 mAb, received escalating, intravenous (IV) doses of PF-3135, once weekly. Prior BCMA-targeted bispecific T-cell engager or chimeric antigen receptor T-cell (CART) treatment was allowed by protocol. Patients had measurable disease per the International Myeloma Working Group (IMWG) updated criteria 2014. A modified toxicity probability interval method (mTPI), targeting a dose-limiting toxicity (DLT) rate of 25% (equivalence interval ± 5%) was used for dose escalation. The primary study objectives are to assess PF-3135 safety and tolerability, to determine the maximum tolerated dose (MTD) and select the recommended phase II dose (RP2D). Secondary objectives include evaluation of anti-myeloma activity, pharmacokinetics (PK), and immunogenicity of PF-3135. Results: As of April 9, 2019, 17 patients had received once weekly, non-continuous, IV infusion of PF-3135 in 6 dose-escalation groups. The majority were men (71%). The median age was 61 yrs (range, 47-82 yrs) and median disease duration since onset was 7 yrs (range, 1.1-13.3 yrs). Ten (59%) patients had ≥1 chromosomal abnormality and 5 (29%) had a normal karyotype (status not known for 2 [12%] patients). The median number of prior anti-myeloma therapies was 11; 5 (29%) patients had received prior BCMA-targeted therapy. Eight (47%) patients had relapsed MM and 8 (47%) had refractory disease (recurrence type not known for 1 [6%] patient). Ten (59%) patients experienced treatment-related (TR) AEs of any grade. Most TRAEs were grade 1-2, including cytokine release syndrome (CRS, 24%), thrombocytopenia (24%), anemia (18%), and pyrexia (18%). Three (18%) patients had grade 3 TRAEs (increased alanine aminotransferase/aspartate aminotransferase, leukocytopenia, neutropenia, and lymphopenia). One patient treated at the highest dose level, who had received prior BCMA CART therapy, developed treatment-related febrile neutropenia, a DLT, which may have been related to CRS and borderline/low neutrophil count at baseline. None of the patients had grade 4-5 TRAEs or discontinued treatment due to a TRAE. The median duration of treatment was 4 (range, 2-12) actual dosing days. Sixteen of the 17 patients were evaluable for response. At the time of data cut-off, one (6%) patient had a minimal response and 6 (35%) patients had stable disease (SD) across dose levels, as best response by investigator IMWG assessment; 9 (53%) patients experienced disease progression. The clinical benefit rate (defined as best response ≥SD) was 41% (95% CI: 18.4%, 67.1%). Conclusions: Treatment with IV PF-3135 was well tolerated at the dose levels evaluated. The observed CRS events were moderate and dose-dependent. Additional dose cohorts are accruing. The latest clinical, biomarker, and PK data will be presented for this ongoing study. Disclosures Raje: Medscape: Honoraria; Research to Practice: Honoraria; Takeda: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AstraZeneca: Research Funding. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Cornell:KaryoPharm: Consultancy; Takeda: Consultancy. Krupka:Pfizer: Employment, Equity Ownership. Navarro:Pfizer: Employment, Equity Ownership. Forgie:Pfizer: Employment, Equity Ownership. Udata:Pfizer: Employment, Equity Ownership. Basu:Pfizer: Employment, Equity Ownership. Chou:Pfizer: Employment, Equity Ownership. Leung:Pfizer: Employment, Equity Ownership. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Serametrix Inc.: Patents & Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Juno: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; Janssen: Research Funding. OffLabel Disclosure: PF-06863135, investigational agent

A phase I study of 17-AAG in relapsed/refractory pediatric patients with solid tumors: A Children’s Oncology Groups study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9018-9018 ◽  
Author(s):  
B. Weigel ◽  
S. Blaney ◽  
J. Kersey ◽  
R. Bagatell ◽  
S. P. Ivy ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Phase I Study ◽  
Drug Exposure ◽  
Mononuclear Cells ◽  
Surrogate Marker ◽  
Hsp90 Inhibition ◽  
Recommended Phase Ii Dose ◽  
Dose Levels

9018 Background: A pediatric phase I study of 17-allylaminogeldanamycin (17-AAG), an Hsp90 inhibitor, was conducted to determine the dose limiting toxicities (DLTs), the recommended phase II dose, the pharmacokinetics (PK), and to evaluate a surrogate marker for Hsp90 inhibition in peripheral blood mononuclear cells (PBMCs). Methods: Cohorts of 3–6 pts were enrolled at dose levels of 150, 200, 270 and 360 mg/m2/dose, administered as a 60 min infusion, on days 1, 4, 8 and 11 of a 21-day cycle. PK and PBMC evaluations were done during the first course of therapy. Results: 17 pts (7 male), median 7 yrs of age (range 1–19), were enrolled. 5 pts who developed PD prior to completing a full cycle of therapy were not considered evaluable for toxicity. No DLTs occurred. Non-DLTs included elevated transaminases (n=6), anemia (n=3), and vomiting (n=3). Based on the adult recommended dose and challenges posed by infusing the large volumes of DMSO, dose escalation was stopped at dose level 4. No CRs or PRs were observed; 3 patients remain on therapy at 6, 7 and 9 months with SD. One patient with hepatoblastoma had a reduction in AFP and SD over 3 cycles. PK data is available from the initial 3 dose levels. Drug exposure increases in proportion to dose for both17-AAG and its metabolite 17-AG. At 270 mg/m2/dose the Cmax and AUC of 17-AAG were 5,303 ± 1,591 ng/ml and 13,150 ± 5,086 ng/ml*hr, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.0 ± 0.5 hrs. Induction of Hsp72, a surrogate marker for inhibition of Hsp90 was detected at all dose levels. Conclusions: The recommended phase II dose of 17AAG is 360mg/m2/day. Non-DMSO formulations may allow for further dose escalation in children and should be studied. No significant financial relationships to disclose.

Phase I study of stereotactic body radiotherapy following radical prostatectomy.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS158-TPS158 ◽  
Author(s):  
Leslie Ballas ◽  
Monish Aron ◽  
Shamim Jhimlee ◽  
Igor Shuryak ◽  
Tanya B. Dorff ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Adverse Events ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Stereotactic Body Radiotherapy ◽  
Phase I Study ◽  
Dose Fractionation ◽  
Level 3 ◽  
Dose Levels

TPS158 Background: Although multiple Phase I/II studies demonstrate safety and low rates of toxicity following stereotactic body radiotherapy (SBRT) to the intact prostate, there are limited data on hypofractionation and SBRT after prostatectomy. This Phase I study was performed to evaluate acute toxicity associated with dose escalation from 3.6 Gy per fraction to 7.1 Gy per fraction to the prostate bed in the post-prostatectomy treatment of prostate cancer. We hypothesize that the toxicity of escalating the dose per fraction to the prostate fossa in the post-operative setting will be well tolerated; and we expect toxicity to be comparable to normal fractionation schedules. Methods: This study (NCT02446366) was designed to look at acute toxicity, defined as toxicity that occurred within the first 10 weeks of RT, of different dose fractionation schemes in the post-prostatectomy setting. The doses chosen for dose escalation on this study are based on an equivalent biological effective dose to a previously published hypofractionated post-prostatectomy study that showed no increase in acute bowel or bladder toxicity. The dose levels are as follows: Level 1 -3.6 Gy x 15 fractions; Level 2- 4.7 Gy x 10 fractions; Level 3 - 7.1 Gy x 5 fractions. Eligibility for participation on the trial was for patients who had pT3N0 disease regardless of margin status in the post-prostatectomy setting, pT2N0 patients with positive margin or with a negative surgical margin and a rising post-operative PSA. Patients could be on concurrent ADT and enroll on this study. Dose was escalated according to a 6+6 schema. For purposes of deciding whether to escalate to a new dose level, expand a dose level or de-escalate from a dose level, we used toxicities and adverse events that occur during the 1st 10 weeks after completion of radiotherapy. Six patients were enrolled on each new dose level with a total of 12 patients required at the maximum tolerated dose. Dose-limiting toxicity (DLT) was defined as grade 3 or worse fatigue, gastrointestinal (GI) or genitourinary (GU) toxicity by Common Terminology Criteria of Adverse Events (version 4.03). Dose levels 1 and 2 have been completed without any DLT. Dose level 3 has enrolled 9/12 patients without any DLT. Clinical trial information: NCT02446366.

scholarly journals OP0205 PHASE I STUDY OF D-0120, A NOVEL URAT1 INHIBITOR IN CLINICAL DEVELOPMENT FOR HYPERURICEMIA AND GOUT

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 127.2-128
Author(s):  
L. Zhang ◽  
D. Wyatt ◽  
K. Stazzone ◽  
Z. Shi ◽  
Y. Wang
Keyword(s):  
Uric Acid ◽  
Phase I ◽  
Healthy Volunteers ◽  
Treatment Period ◽  
Serum Uric Acid ◽  
Dose Escalation ◽  
Phase I Study ◽  
Proportional Increase ◽  
Dose Levels ◽  
Dose Proportional

Background:D-0120 is a novel oral selective uric acid transporter (URAT1) inhibitor being developed for the treatment of hyperuricemia and gout by blocking the reabsorption of uric acid (UA) within the renal proximal tubule, thereby reducing serum uric acid concentrations. As a novel URAT1 inhibitor, D-0120 is anticipated to have more potent serum UA reducing effect than the approved URAT1 inhibitor lesinurad, but with less toxicity and wider therapeutic window. The pharmacological potential of D-0120 for the treatment of hyperuricemia and gout was demonstrated in preclinical studies. The results of the in vitro hURAT1 expressed CHO cell model showed that the inhibitory activity of D-0120 is 150-fold more potent than lesinurad and slightly more potent than verinurad.Objectives:The purpose of this dose escalation study is to evaluate the safety and tolerability of D-0120 in multiple ascending doses in healthy volunteer, to characterize the pharmacokinetics (PK) of D-0120 and to assess pharmacodynamic (PD) effects and determine the drug-drug interaction (DDI) effect of febuxostat and D-0120 in healthy volunteers.Methods:This is a randomized, double blind, multiple ascending doses Phase I study of D-0120 in healthy volunteers conducted at one site. Thirty-two healthy eligible volunteers with serum uric acid level ≥ 4.5 mg/dL but within normal range at screening were enrolled and dosed with D-0120 within 4 different single agent cohorts for a period of 7 days. Each cohort had 8 subjects randomized at 3:1 ratio for D-0120:placebo. A fifth cohort of 8 healthy eligible volunteers were enrolled and dosed with 5 mg of D-0120 in combination with 40 mg of febuxostat over a period of 9 days. Evaluation of safety, PK and PD was conducted at various timepoints while the patients were in confinement. Further safety evaluation took place on Day 14. A Safety Review Committee reviewed safety, PK and PD data for each cohort of D-0120 dose level (2.5 mg, 5 mg, 10 mg, 20 mg) as well as when D-0120 5 mg was combined with 40 mg febuxostat. PK evaluation for multiple dose parameters included AUC0-τ, Cmax, Cmin, Tmax and Fl.Results:Dose escalation of D-0120 from 2.5 mg/day to 20 mg/day was completed without any dose limiting toxicities. Most AEs occurred during the study were mild to moderate in severity and did not require any treatment before resolution. There was no SAE and no dose reduction during the treatment period. The pharmacokinetic (PK) evaluation of ascending dose levels of D-0120 suggested a dose proportional increase in drug exposure and there was no significant change of PK profile between Day 1 and Day 7 of dosing. For pharmacodynamic (PD) evaluation, the serum uric acid (UA) levels before and after D-0120 dosing was evaluated on multiple days. The UA reduction effect achieved maximum at about 4-8 hours after dosing and the effect lasted for at least 24 hours. After the 7-day dosing period, the mean percentage of UA reduction from baseline showed an increasing trend as the dose level increased.More detailed safety, PK and PD data from multiple D-0120 dose cohorts and D-0120/febuxostat combination cohort will be presented at the meeting.Conclusion:The oral daily administration of a novel URAT1 inhibitor, D-0120, in healthy volunteers for 7 days was well tolerated at dose levels from 2.5 mg/day to 20 mg/day. The PK profile demonstrated a dose proportional increase. D-0120 administration for 7 days resulted in significant reduction of serum UA levels. Further evaluation of this novel agent in longer treatment period and in patients with hyperuricemia and/or gout is warranted.References:Not Applicable.Disclosure of Interests:Ling Zhang Employee of: INVENTISBIO, David Wyatt: None declared, Kathryn Stazzone Employee of: INVENTISBIO, Zhe Shi Employee of: INVENTISBIO, Yaolin Wang Employee of: INVENTISBIO

scholarly journals A Phase I, Open-Label Study to Evaluate the Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity of PF-06863135, a B-Cell Maturation Antigen/CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Advanced Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3229-3229 ◽  
Author(s):  
Alexander M. Lesokhin ◽  
Noopur Raje ◽  
Cristina J Gasparetto ◽  
Justine Walker ◽  
Heike I. Krupka ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase I Study ◽  
Cell Maturation ◽  
Open Label ◽  
B Cell Maturation ◽  
Dose Levels ◽  
B Cell Maturation Antigen

Abstract Background: Despite a number of recent advances in the treatment of multiple myeloma (MM), the majority of patients are likely to relapse or become resistant to current treatment options. PF-06863135 (PF-3135) is a humanized immunoglobulin G (IgG) CD3 bispecific monoclonal antibody that utilizes anti-B-cell maturation antigen (BCMA) and anti-CD3 targeting arms paired through hinge-mutation technology within an IgG2a backbone. The molecule binds to BCMA-expressing myeloma cell lines and to T cells with affinities of 20 pM and ~40 nM, respectively (Panowski et al. Blood 2016). PF-3135 has a half-life of ~4-6 days in cynomolgus monkeys, which is predicted to be similar in humans (Panowski et al. Blood 2016). This is an ongoing open-label, multidose, multicenter, dose-escalation phase I study to assess the safety, pharmacokinetics (PK), and pharmacodynamics of PF-3135 in adult patients with advanced MM who have relapsed from, or are refractory to, standard therapy (ClinicalTrials.gov, identifier: NCT03269136). Methods: Patients aged ≥18 years with relapsed or refractory MM and measurable disease (as per International Myeloma Working Group updated criteria 2014), who have received prior therapy that included a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody, either in combination or as a single agent, received escalating doses of PF-3135 intravenously. The primary objectives include assessment of safety and tolerability at increasing dose levels of PF-3135 to estimate the maximum tolerated dose and select the recommended phase 2 dose (RP2D). Secondary objectives include evaluation of the overall safety profile, anti-myeloma activity, PK, and immunogenicity of PF-3135. A modified toxicity probability interval method, which targets a dose-limiting toxicity rate of 25% with an acceptable equivalence interval (± 5%), is utilized for dose escalation. Results: Five patients have received PF-3135 in the dose-escalation portion of the study. No dose-limiting toxicities or cytokine-release syndrome events have been reported. One patient experienced a grade 1 fever (not related to PF-3135) that was reported as a serious adverse event (AE) because the patient was hospitalized for observation. The majority of reported treatment-emergent AEs (all-causality) have been grade ≤2. One patient experienced acute grade 3 alanine aminotransferase/aspartate aminotransferase elevation (<5 days' duration) following Cycle 1 Day 1 dosing, which was considered related to study drug. To date, all reported AEs are as expected for the patient population. Conclusion: PF-3135 has been well tolerated at the dose levels studied in the ongoing phase I study to date. This encouraging safety profile supports the continued study of higher dose levels to select the RP2D. Updated clinical trial data will be presented in the poster. Disclosures Lesokhin: Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Serametrix, inc.: Patents & Royalties: Royalties; Janssen: Research Funding; Genentech: Research Funding. Raje:BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy; AstraZeneca: Research Funding; Research to Practice: Honoraria; Medscape: Honoraria; Amgen Inc.: Consultancy. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Janssen: Consultancy, Honoraria, Other: Travel; Takeda: Honoraria. Walker:Pfizer Inc: Employment. Krupka:Pfizer Inc: Employment. Joh:Pfizer Inc: Employment. Taylor:Pfizer Inc: Employment, Equity Ownership. Jakubowiak:Karyopharm: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria.

A Phase I Dose Escalation Study Of TGR-1202, a Novel PI3K-δ Inhibitor, For Patients With Relapsed Or Refractory Hematologic Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4373-4373 ◽  
Author(s):  
Michael Savona ◽  
Martin Gutierrez ◽  
Mark Lanasa ◽  
Changchun Deng ◽  
John Kuhn ◽  
...  
Keyword(s):  
Phase I ◽  
Disease Progression ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Prior Treatment ◽  
Pharmacokinetic Parameters ◽  
Employment Equity ◽  
Equity Ownership ◽  
Dose Levels

Abstract Background PI3K-δ is highly expressed in cells of hematopoietic origin and is often upregulated in lymphoid malignancies. TGR-1202 is a novel, next generation PI3K-δ inhibitor shown to inhibit Akt phosphorylation and induce apoptosis in lymphoma and leukemia cell lines, displaying activity in numerous pre-clinical models with potentially superior pharmacokinetic (PK) properties to other PI3K-δ inhibitors in development, including an extended half-life observed in pre-clinical animal studies. In addition, the chemical structure of TGR-1202 was designed specifically to avoid heterocylic nitrogen moieties in the backbone of the molecule, known to interact with hepatic enzymes, in an effort to mitigate a class effect of hepatotoxicity. Herein we present preliminary results of a Phase I, first in human, open label study of the oral PI3K-δ inhibitor, TGR-1202. Methods The dose escalation portion of the study will determine the maximum tolerated dose (MTD) of TGR-1202 using a standard 3+3 dose escalation design. Patients (pts) with a confirmed diagnosis of B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), peripheral T-cell lymphoma, or other lymphoproliferative disorders previously treated with at least one prior therapy are eligible. Additional eligibility criteria include ECOG PS ≤ 2 and measurable/evaluable disease. Primary endpoints are safety and PK measurement; secondary endpoints include pharmacodynamic (PD) analysis and efficacy (overall response rate). TGR-1202 will be administered orally QD until unacceptable toxicity, disease progression, or withdrawal from treatment. Treatment cycles are 28 days. Efficacy evaluations are planned every 8 weeks. AEs are assessed using the CTCAE v4.0. For pts with CLL/SLL, hematologic toxicity is graded according to IWCLL guidelines. Results Thirteen patients have been enrolled to date across 4 dose levels: QD 50mg, 100mg, 200mg, and 400mg. Pts are 83% male, ECOG 0/1: 54%/46%, with a median age of 69 yrs (range: 49-82). Patients had a median of 2 (range: 1-5) prior treatment regimens, and 38% were refractory to prior treatment. Lymphoma histologies include follicular lymphoma (5 pts), CLL/SLL (4 pts), and lymphoplasmacytic lymphoma, mantle cell lymphoma, DLBCL, and atypical hairy cell leukemia (1 pt each). Twelve of the thirteen patients are evaluable for DLT assessment (one patient in Cohort 1 was replaced within first week of treatment due to rapid disease progression). Of the 12 evaluable patients, 8 are currently on study; 4 patients discontinued treatment due to disease progression. To date, there have been no DLTs. One patient experienced G3 neutropenia and thrombocytopenia which resulted in a dose reduction. No other G3/4 related hematologic or non-hematologic toxicities have been observed. Notably, aside from unrelated G1 elevation of GGT in one patient, there has been no hepatotoxicity. Of the 7 patients who completed 2 cycles of treatment (8 wks) at 200mg daily dosing or less, 3 (43%) showed SD and 4 (57%) had PD. Five additional patients have not reached their first response assessment. TGR-1202’s preliminary mean pharmacokinetic parameters determined on Day 1 of Cycle 1 (table) are: median Tmax of 2 hrs (range 1-8hrs), harmonic mean t1/2 of 13 (± 8.06) hr, and CL/F of 48.97 (± 15.6) L/hr. CL values over the 4 dose levels are independent of dose (r = 0.07, p > 0.20). A linear relationship (Spearman’s) exists between dose and both AUC (r = 0.95) and Cmax (r = 0.80). Steady-state levels are reached by Day 15. The ave. accumulation Cmin ratio between Cycle 1 t24hr & Cycle 2 t0hr is 8 (± 2.65). Conclusions To date, TGR-1202 has been well tolerated in patients with relapsed/refractory hematologic malignancies. There have been no DLTs observed and toxicities have been minimal to date. Enrollment continues at higher dose cohorts. Updated safety, efficacy, PK, and PD data will be presented. Disclosures: Lanasa: Rhizen Pharmaceuticals S A: Research Funding. Kuhn:TG Therapeutics, Inc.: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc. : Employment, Equity Ownership. Vakkalanka:Rhizen Pharmaceuticals S A: Employment, Equity Ownership.

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