Phase 1 single-center, dose escalation study of D2C7-IT administered intratumorally via convection-enhanced delivery for adult patients with recurrent malignant glioma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13532-e13532 ◽  
Author(s):  
Dina Randazzo ◽  
Annick Desjardins ◽  
Vidyalakshmi Chandramohan ◽  
John H. Sampson ◽  
Katherine B. Peters ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Genetically Engineered ◽  
Convection Enhanced Delivery ◽  
Dose Escalation Study ◽  
Who Grade ◽  
Recombinant Immunotoxin ◽  
Level 3 ◽  
Grade 3

e13532 Background: D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin consisting of EGFR-wt and EGFRvIII monoclonal antibodies with a genetically engineered Pseudomonas exotoxin, PE-38KDEL. The primary objective is to determine the maximum tolerated dose of D2C7-IT when delivered intratumorally by convection enhanced delivery (CED). Methods: Inclusion criteria includes subjects with a single, recurrent supratentorial WHO grade III or IV glioma, KPS ≥ 70 and a washout of chemotherapy, bevacizumab or study drug of ≥ 4 weeks. Prior to administration of D2C7-IT, recurrent tumor must be confirmed by histopathology. A minimum of 2 subjects are accrued by dose level. Results: Currently, 23 subjects have been treated (16 male, 7 female) with a median age of 54 years. Out of 9 dose levels, 2 subjects have been treated at every dose except for 4 at dose level 3 (120 ng/ml) and 5 at dose 6 (405ng/ml). Adverse events possibly, probably or definitely related to D2C7-IT are mostly grade 1 or 2 events consisting of, but not limited to: intracranial hemorrhage (n = 1), stroke (n = 2), headache (n = 15), seizure (n = 5), confusion (n = 4), paresthesia (n = 4), dysarthria (n = 1), dysphasia (n = 4), visual disturbances (n = 7), fatigue (n = 4), gait disturbance (n = 2), elevated transaminases (n = 5), decreased platelets (n = 3), decreased neutrophil count (n = 1), nausea (n = 3), vomiting (n = 1), and thromboembolic event (n = 1). There was 1 dose limiting toxicity (grade 4 seizure at dose level 3), 2 grade 3 headaches and 1 grade 3 elevated ALT. 14 subjects are still alive with 6 remaining on study. So far, the longest survival time from infusion is 18.2+ months. Conclusions: D2C7-IT infusion via CED is safe with encouraging results. This dose escalation Phase I study is ongoing and will set the stage for the Phase II trial. Clinical trial information: NCT02303678.

scholarly journals ATIM-24. DOSE FINDING AND DOSE EXPANSION TRIAL OF D2C7 IMMUNOTOXIN (D2C7-IT) ADMINISTERED INTRATUMORALLY VIA CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMA (MG)

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi6-vi6
Author(s):  
Annick Desjardins ◽  
Dina Randazzo ◽  
Vidya Chandramohan ◽  
Katherine Peters ◽  
Margaret Johnson ◽  
...  
Keyword(s):  
Dose Level ◽  
Cerebral Edema ◽  
Phase 1 ◽  
Dose Range ◽  
Antibody Fragment ◽  
Genetically Engineered ◽  
Phase 2 ◽  
Who Grade ◽  
Recombinant Immunotoxin ◽  
Grade 3

Abstract BACKGROUND D2C7-IT is a recombinant immunotoxin comprised of a dual-specific antibody fragment targeting EGFRwt and EGFRvIII and a genetically engineered form of the Pseudomonas exotoxin, PE38-KDEL. We report results of a phase 1 trial, with dose expansion at the selected phase 2 dose, evaluating D2C7-IT delivered intratumorally by CED. METHODS Eligible patients are adults with recurrent supratentorial WHO grade III or IV MG; solitary tumor; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS >70%. Two patients per dose level (DL) were to be enrolled in the dose escalation portion (dose range: 40ng/mL to 23,354ng/mL), followed by dose expansion at the selected phase 2 dose (DL13). RESULTS As of 6/07/2019, 51 patients have been treated; 10 patients on the phase 2 dose. Observed dose limiting toxicities include: grade 4 seizure (n=1) on DL3, grade 3 confusion and pyramidal tract syndrome (n=1) on DL13, and grade 4 cerebral edema (n=1) and grade 3 dysphasia (n=1) on DL17. Grade 3 or higher adverse events possibly related to D2C7-IT include: seizure (grade 4, n=2, grade 3, n=3), cerebral edema (grade 4, n=1), hydrocephalus (grade 3, n=5), headache (grade 3, n=4), hemiparesis (grade 3, n=4), dysphasia (grade 3, n=4), lymphopenia (grade 3, n=3), thromboembolic event (grade 3, n=3); and one each of grade 3 elevated ALT, urinary tract infection, fall, wound complication, generalized muscle weakness, confusion, encephalopathy, and somnolence. Fourteen patients are alive. Three patients have partial radiographic response and remain alive without additional therapy more than 46, 27 and 21 months after D2C7-IT infusion. CONCLUSION Dose level 13 was selected as the optimal phase 2 dose and patient accrual is ongoing on the dose expansion arm. Encouraging efficacy results have been observed. A trial of D2C7-IT with checkpoint inhibitor is planned to start in the near future.

scholarly journals CTIM-23. A PHASE 1 TRIAL OF D2C7-IT IN COMBINATION WITH ATEZOLIZUMAB IN RECURRENT WHO GRADE IV MALIGNANT GLIOMA (MG)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii38-ii38
Author(s):  
Annick Desjardins ◽  
Dina Randazzo ◽  
Vidya Chandramohan ◽  
Katherine Peters ◽  
Margaret Johnson ◽  
...  
Keyword(s):  
Immune Responses ◽  
Phase 1 ◽  
Antibody Fragment ◽  
Study Drug ◽  
Genetically Engineered ◽  
Convection Enhanced Delivery ◽  
Dose Escalation Study ◽  
Who Grade ◽  
Recombinant Immunotoxin ◽  
Grade Iii

Abstract BACKGROUND D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin comprising an EGFR-wt and mutant-specific (EGFRvIII) monoclonal antibody fragment and a genetically engineered form of the pseudomonas exotoxin. When injected directly into the tumor mass by convection enhanced delivery (CED), in addition to direct tumor cell killing, immunotoxins induce secondary immune responses by the activation of CD4+ and CD8+ T-cells. We completed a phase 1 dose escalation study of D2C7-IT injected by CED into recurrent WHO grade III-IV MG and identified the phase 2 dose (6,920 ng/mL). Three patients remain in partial response more than 58, 38, and 32 months after a single D2C7-IT intratumoral infusion. As optimal induction of anti-tumor immune responses by immunotoxins is impeded by potent MG-mediated immunosuppression, we are assessing the toxicity of the combination of D2C7-IT with atezolizumab in patients with recurrent WHO grade IV MG. METHODS Eligibility includes adult patients with recurrence of a solitary supratentorial WHO grade IV MG; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS >70%. Patient receives an intratumoral infusion of D2C7-IT and initiates two weeks later atezolizumab at 1200mg, followed by atezolizumab every 3 weeks for up to 2 years. Two cohorts of 3 patients are initially accrued to assess the toxicity of the combination. Assuming accrual continues after the initial two cohorts of 3 patients, an additional 12 patients will be accrued to the study. RESULT The first enrolled patient experienced a grade 3 DLT (grade III ALT elevation) after the first infusion of atezolizumab, but showed a more extensive immunotherapeutic effect by imaging than observed with patients on the D2C7-IT monotherapy trial. Enrollment is ongoing. CONCLUSION D2C7-IT monotherapy has shown prolonged survival and disease control in some patients. We are now evaluating the combination of D2C7-IT with checkpoint inhibition.

Deflexifol (a novel formulation of 5FU): Phase 1 dose escalation study of infusional and bolus schedules after failure of standard treatment.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2529-2529
Author(s):  
Philip R. Clingan ◽  
Stephen P. Ackland ◽  
Marie Ranson ◽  
Daniel Brungs ◽  
Morteza Aghmesheh ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Standard Treatment ◽  
Phase 1 ◽  
Liver Function Tests ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Advanced Malignancy ◽  
Grade 3

2529 Background: 5-Fluorouracil (5FU) is administered in combination with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible as 5FU and LV are chemically incompatible, so the maximum possible interaction for benefit is not achieved Deflexifol, an all in one formulation of 5FU/LV with cyclodextrin (HP-β-CD 100mg/ml, 5-FU 15mg/ml & LV 1mg/ml) at physiological pH, was developed to improve efficacy and tolerance. Methods: A phase I dose-escalation trial to assess the safety, tolerability, MTD and DLT of Deflexifol given in two schedules has been completed. Secondary objectives included the pharmacokinetic (PK) profile and efficacy outcomes. Cohorts of patients with advanced malignancy after failure of standard treatment received Deflexifol as 46-h infusion Q2W or bolus weekly x6 in a standard 3+3 phase I design with no intra-patient dose escalation from dose level 1: 375mg/m² bolus or 1200mg/m² infusional up to dose level 5: 575mg/m² bolus or 3600mg/m² infusional. PK sampling of 5FU and dihydroFU was conducted on all patients to assess PK variability and adequacy of dosing. Results: 40 patients (21 infusional, 19 bolus) with breast (7), colorectal (24), other GI (6) & NSCLC (3) received a total 293 courses of treatment. No > grade 1 toxicity was noted at 375-475 mg/m2 bolus, or at 1200-2400 mg/m2 infusion. The DLT in bolus schedule was grade 3 diarrhea and myelosuppression at 575 mg/m2, with no DLT in the infusion schedule at the maximum dose 3600 mg/m2. The MTD have been established for both treatment arms: bolus 525mg/m²; 46-h infusion 3,600mg/m², with no grade IV toxicity observed. Other grade 3 toxicities were nausea, vomiting, and raised liver function tests. 5FU PK in this mixture is similar to 5FU alone. Encouraging efficacy results were seen with partial response in 1 patient and stable disease in 23 patients. Median PFS was (12.3 wks) and OS was (24.8 wks). Conclusions: Deflexifol has little toxicity and is effective in bolus and infusion schedules at doses equal to or greater than those feasible with 5FU and LV infused separately. A first-line phase II study in combination with oxaliplatin is planned. Clinical trial information: 044867.

scholarly journals EPCT-02. PBTC-051: FIRST IN PEDIATRICS PHASE 1 STUDY OF CD40 AGONISTIC MONOCLONAL ANTIBODY APX005M IN PEDIATRIC SUBJECTS WITH RECURRENT/REFRACTORY BRAIN TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii304-iii304
Author(s):  
Holly Lindsay ◽  
Arzu Onar-Thomas ◽  
Mehmet Kocak ◽  
Tina Young Poussaint ◽  
Girish Dhall ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Dose Level ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Pediatric Brain Tumor ◽  
Cns Tumors ◽  
Level 3 ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Antigen Presenting

Abstract BACKGROUND CD40 is a co-stimulatory molecule expressed on antigen presenting cells (APCs). APX005M is a CD40 agonist monoclonal antibody which stimulates innate and adaptive anti-tumor immunity through activation of APCs, macrophages, and antigen-specific CD8+T-cells. Pediatric Brain Tumor Consortium study PBTC-051 is the first investigation of APX005M in pediatric patients and is evaluating the safety, recommended phase 2 dose (RP2D), pharmacokinetics, and preliminary efficacy of APX005M in children with central nervous system (CNS) tumors. RESULTS Accrual of patients with recurrent/refractory primary malignant CNS tumors (stratum 1) began in March 2018. 16 patients (2 ineligible) have enrolled on this stratum; 14 were treated. Dose escalation through 3 planned dose levels of APX005M was completed without excessive or unanticipated toxicities. The highest dose level (0.6 mg/kg q3 weeks) is the presumptive RP2D, and an expansion cohort is currently enrolling at this dose. 2 patients at dose level 3 have received >12 cycles of therapy. Grade 3 or higher adverse events at least possibly attributable to APX005M include 11 lymphopenia, 5 neutropenia, 5 leukopenia, 3 ALT elevations, 1 AST elevation, 1 thrombocytopenia, and 1 hypoalbuminemia. PK data will be available March 2020. Stratum 2 is now enrolling patients with post-radiation/pre-progression DIPG beginning at dose level 2, with 1 patient currently enrolled. CONCLUSION The CD40 agonistic antibody APX005M has demonstrated preliminary safety in pediatric patients with recurrent/refractory primary malignant CNS tumors and has a likely RP2D of 0.6 mg/kg q3 weeks in this population. Preliminary efficacy data are pending.

scholarly journals Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer

2020 ◽  
Vol 38 (6) ◽  
pp. 1836-1845
Author(s):  
Shunsuke Kondo ◽  
Masaomi Tajimi ◽  
Tomohiko Funai ◽  
Koichi Inoue ◽  
Hiroya Asou ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Mammalian Target Of Rapamycin ◽  
Japanese Patients ◽  
Competitive Inhibitor ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Dual Inhibitor ◽  
Advanced Malignancies ◽  
Grade 3

Summary LY3023414 is an oral, selective adenosine triphosphate-competitive inhibitor of class I phosphatidylinositol 3-kinase isoforms, mammalian target of rapamycin, and DNA-protein kinase in clinical development. We report results of a 3 + 3 dose-escalation Phase 1 study for twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to evaluate tolerability and safety of LY3023414. Secondary objectives were to evaluate pharmacokinetics and to explore antitumor activity. A total of 12 patients were enrolled and received 150 mg (n = 3) or 200 mg (n = 9) LY3023414 BID. Dose-limiting toxicities were only reported at 200 mg LY3023414 for 2 patients with Grade 3 stomatitis. Common treatment-related adverse events (AEs) across both the dose levels included stomatitis (75.0%), nausea (66.7%), decreased appetite (58.3%), diarrhea, and decreased platelet count (41.7%), and they were mostly mild or moderate in severity. Related AEs Grade ≥ 3 reported for ≥1 patient included anemia, stomatitis, hypophosphatemia, and hyperglycemia (n = 2, 16.7%). Two patients discontinued due to AEs (interstitial lung disease and stomatitis). No fatal events were reported. The pharmacokinetic profile of LY3023414 was characterized by rapid absorption and elimination. Five patients had a best overall response of stable disease (150 mg, n = 3; 200 mg, n = 2) for a 55.6% disease control rate. LY3023414 up to 200 mg BID is tolerable and safe in Japanese patients with advanced malignancies.

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 1 study of CPX-1, a fixed ratio formulation of irinotecan (IRI) and floxuridine (FLOX), in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2014-2014 ◽  
Author(s):  
G. Batist ◽  
K. Chi ◽  
W. Miller ◽  
S. Chia ◽  
F. Hasanbasic ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Fixed Ratio ◽  
Compression Fracture ◽  
Drug Combinations ◽  
Molar Ratio ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

2014 Background: In vitro studies have shown that varying the ratio of individual agents in drug combinations can result in synergistic, additive or antagonistic activity against tumor cells. CPX-1 is a liposomal formulation of IRI and FLOX in a fixed 1:1 molar ratio which was selected as optimal in vitro and confirmed to be synergistic in vivo in preclinical tumor models. CPX-1 overcomes the dissimilar pharmacokinetics (PK) of the individual drugs, enables sustained maintenance of this ratio after IV administration, and was evaluated in a Phase I open-label, dose-escalation study. Methods: Starting dose was 30 U/m2 (1 Unit of CPX-1 contains 1 mg IRI + 0.36 mg FLOX) given on day 1 and 15 of each 28-day cycle. Dose escalation was by modified Fibonacci with 4 subjects/cohort. Eligibility included: ≥ 18 yo; advanced solid tumor; ECOG PS ≤ 2; adequate bone marrow/liver/renal function. PK analysis was done on day 1 and 15 of the first cycle. Results: 26 subjects (16M:10F), median age 54.5 y (21–72), all with prior therapy, enrolled in 6 cohorts with the 5th cohort expanded to 6 subjects. Diagnoses: 8 colorectal, 3 pancreatic, 3 ovarian, 2 breast, 2 gastric, 2 esophageal, 2 sarcomas, 1 renal cell, 1 prostate, 1 NSCLC and 1 sphenoid sinus. Response: 20 subjects evaluable: 2 confirmed PRs (NSCLC 8+ wks; Colon 13+ wks, in a patient with prior IRI exposure) and 13 with SD (8–24+wks). Safety: DLTs were observed at the 6th dose level: 4 subjects with DLTs: 3 diarrhea (one resulting in death due to dehydration/ARF) and one neutropenia. Other possibly related grade 3 and 4 events included one each of: grade 3 diarrhea, grade 3 vomiting, grade 3 neutropenia, grade 3 fatigue, grade 3 compression fracture and arthralgia and pulmonary embolism grade 4. PK: In all 14 subjects analyzed to date the 1:1 molar ratio of IRI to FLOX was maintained for 24 hours and metabolites 5-FU and SN-38 were present in the plasma. Conclusions: CPX-1 represents a new approach to developing drug combinations in which drug ratios are pre-selected in vitro based on optimal antitumor activity and maintained systemically through pharmacokinetic control. Phase 2 studies are planned with a recommended dose of 210U/m2 of CPX-1. [Table: see text]

Phase 1 dose escalation study of MEDI-565, a bispecific T-cell engager that targets human carcinoembryonic antigen (CEA), in patients with advanced gastrointestinal (GI) adenocarcinomas.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 320-320
Author(s):  
Michael J. Pishvaian ◽  
Michael Morse ◽  
Jennifer T. McDevitt ◽  
Song Ren ◽  
Gabriel Robbie ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Dose Escalation ◽  
Half Life ◽  
High Titer ◽  
Phase 1 ◽  
Single Chain ◽  
Dose Escalation Study ◽  
Human T Cell ◽  
Grade 3

320 Background: MEDI-565, a bispecific single-chain antibody, targets human CEA on tumor cells and the CD3 epsilon subunit of the human T-cell receptor complex. In murine models, MEDI-565 showed antitumor activity in CEA-expressing tumors (J Immunother 2009;34:341-52). Methods: This phase 1, multicenter, open-label, dose-escalation study enrolled adults with GI adenocarcinomas (including esophageal, gastric, small intestine, colorectal, biliary tract, and pancreatic). MEDI-565 was given intravenously over 3 h on days 1–5 in 28-day cycles, with 4 single-patient (pt) (0.75–20 μg) and 5 standard 3+3 escalation (60 μg–3 mg; 1.5–7.5 mg with dexamethasone [dex]) cohorts. Primary objective was to determine the maximum tolerated dose (MTD); secondary objectives were to evaluate pharmacokinetics (PK), antidrug antibody (ADA), and antitumor activity. Results: Study enrolled39 pts: mean age 59 y; 56% male; 28 (72%) colorectal, 6 (15%) pancreatic, 5 (13%) other. Dose-limiting toxicities (grade ≥ 3 nonhematologic) were seen in 4 pts (2 at 3-mg; 2 at 7.5-mg + dex): hypoxia (n = 2), diarrhea, and cytokine release syndrome (CRS). Grade 3 treatment-related adverse events (AEs) seen in 5 pts: diarrhea, CRS, increased alanine aminotransferase, hypertension (all n = 1), and hypoxia (n = 2). Treatment-related serious AEs seen in 6 pts: diarrhea, vomiting, pyrexia, CRS (all n = 1), and hypoxia (n = 2). Five pts discontinued treatment due to AEs: diarrhea, CRS, central nervous system metastases, and hypoxia (n = 2). MEDI-565 exposures increased in approximately dose-proportional manner, with clearance (35–77 L/d) and half-life (2–7 h) typical of drug class. ADA had minor impact; 19 pts (48.7%) had ADAs, 5/39 (12.8%) with high titer, with decreased MEDI-565 concentrations in 2 pts. Plasma inflammatory cytokines were elevated posttreatment in several pts at 1.5- and 3-mg (no dex) dose levels. No objective responses were observed; 11 (28%) pts had stable disease as best response. Conclusions: The MTD of MEDI-565 in pts with GI adenocarcinomas was 5 mg with dex. PK was linear, with fast clearance and short half-life. No objective responses were observed. Clinical trial information: NCT01284231.

scholarly journals Pralatrexate in Combination with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Previously Untreated Patients with Peripheral T-Cell Lymphoma (PTCL): A Phase 1 Dose-Escalation Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 818-818 ◽  
Author(s):  
Andrei Shustov ◽  
Patrick B Johnston ◽  
Stefan Klaus Barta ◽  
Gajanan Bhat ◽  
Guru Reddy ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Dose Escalation Study ◽  
Chop Regimen ◽  
Treatment Naïve ◽  
Grade 3

Abstract Background: The prognosis of patients with PTCL remains poor after standard CHOP therapy - the most commonly used combination regimen. Relapses occur in the majority of patients, and curability rates of the relapsed disease are very low. Hence, advances in front-line therapy of PTCL are long overdue. Pralatrexate, a second-generation antifolate, demonstrated a single agent activity in patients with relapsed and refractory PTCL with a response rate of 27%, including complete remissions in 11% of patients (O'Connor et al. J Clin Onc 2011). We conducted a Phase 1 multi-center dose-escalation study of pralatrexate in combination with standard CHOP (Fol-CHOP) in treatment-naïve PTCL patients. Objectives: The primary objective of the study was to determine the maximum tolerated dose (MTD) of pralatrexate when administered with a standard CHOP regimen to patients with newly diagnosed PTCL. The secondary objectives included safety, tolerability, efficacy and pharmacokinetics of pralatrexate in combination with CHOP (Fol-CHOP). Methods: In Part 1 of this 3+3 dose-escalation study, pralatrexate was administered at 10, 15, 20, 25, or 30 mg/m2 as an IV push on days 1 and 8 of a standard 21-day CHOP regimen (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [maximum 2 mg] on day 1 and oral prednisone 100 mg on days 1-5). In Part 2 of the study patients were treated at the MTD of pralatrexate established in Part 1, with standard CHOP. In both parts of the study patients were treated with up to 6 cycles of therapy, or until toxicity or disease progression. Patients received antimicrobial prophylaxis, myeloid growth factor support, and "leucovorin rescue" throughout 6 cycles of therapy. Dose-limiting toxicities (DLT) were considered during the 1st cycle of Fol-CHOP and included: Grade 4 infections, treatment-related non-hematological toxicity ≥Grade 3, platelet count < 25 X 109/L at any time, or ANC < 0.5 X 109/L for >7 days despite G-CSF administration. Responses were assessed by the investigator per the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: A total of 31 patients have been enrolled (19 in Part 1; 12 in Part 2). MTD was not reached and pralatrexate dose of 30 mg/m2 in combination with CHOP was selected for Part 2 of the study as predefined by the protocol. The majority of patients were male, White, with the median age of 66 yrs (range, 18-78) at the time of enrolment. PTCL diagnoses included: anaplastic large cell lymphoma, anaplastic lymphomakinase-negative (ALCL, ALK-, n=5), peripheral T-cell lymphoma, not-otherwise specified (PTCL-NOS, n=18), and angioimmunoblastic T-cell lymphoma (AITL, n=5). Fol-CHOP was generally well tolerated with median RDI of 98%. Common (≥ 30%) adverse events (AEs) of any grade were fatigue (n=23), constipation (n=20), nausea (n=16), mucositis (n=14), diarrhea (n=12), anemia (n=9), vomiting (n=10) and oral pain (n=10). Most common (≥ 10%) AEs ≥ grade 3 were anemia (n=6), fatigue (n=4) and neutrophil count decreas (n=5). The only Grade >3 treatment-related AEs (≥10%) was neutrophil count decrease (n=4). SAEs were observed in 13 patients, treatment related SAEs were anemia, febrile neutropenia, dehydration, mucositis and nausea. Five patients withdrew from study: 2 due to disease progression, 1 due to AE and 2 due lapse >28 days between doses. In the 27 patients avaluable for response, the investigator assessed objective response (OR) and complete response (CR) rates were 89% wand 67%, respectively. Conclusions: The combination of pralatrexate and CHOP was well tolerated in treatment-naive PTCL patients. MTD of pralatrexate was not reached, and the protocol-defined maximum dose of 30 mg/m2 on days 1 and 8 of a 21-day CHOP cycle was recomended for future studies. The observed OR and CR rates warrant further evaluation of this regimen in newly diagnosed PTCL patients. Disclosures Shustov: Celgene: Other: Publication assistance; Spectrum Pharmaceuticals: Consultancy, Research Funding. Bhat: Spectrum Pharmaceuticals: Employment. Reddy: Spectrum Pharmaceuticals: Employment.

Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory lymphoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8518-8518 ◽  
Author(s):  
Steven M. Horwitz ◽  
Ian Flinn ◽  
Manish R. Patel ◽  
Anas Younes ◽  
Francine M. Foss ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Early Results ◽  
Refractory Lymphoma ◽  
Grade 3

8518 Background: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. IPI-145, a potent oral inhibitor of the PI3KEδ and PI3K-γ isoforms, is in clinical development for patients (pts) with hematologic malignancies. Early results in pts with relapsed/refractory lymphoma from an ongoing Phase 1 study are reported here. Methods: This dose-escalation study evaluates the safety, maximum tolerated dose (MTD), clinical activity, and pharmacokinetics (PK) of IPI-145. Expansion cohorts (EC) < MTD are allowed. IPI-145 is given orally twice daily (BID) in 28-day cycles. Tumor response is based on standard disease-specific criteria. Results: 55 pts have been dosed with IPI-145. PK, available through 50 mg BID, are linear with complete inhibition of PI3K-δ at doses > 15 mg BID and increasing suppression of PI3K-γ with increasing dose. In the 36 pts with lymphoma who received 15 mg to 75 mg BID, the median [range] number of cycles was 2.4 [0.1–10] and 67% remain on study. Treatment-related adverse events (TRAEs) occurred in 50% of pts with lymphoma. Neutropenia and increased ALT were the most common ≥ Grade 3 TRAEs (4 pts each) and were not associated with increasing dose. > Grade 3 ALT elevations were more common in lymphoma pts (18%) compared to non-lymphoma pts (5%). Among evaluable pts with lymphoma (n=27), early clinical activity was observed in T-cell (n=6, 1 CR, 1 PR, 1 SD) and aggressive/indolent B-cell (n=21, 2 CR, 9 PR, 5 SD) lymphoma pts at ≤ 75 mg BID. 92% of responses were observed by 3 months. Conclusions: IPI-145 appeared well tolerated and has shown clinical activity in pts with relapsed/refractory advanced B- and T-cell lymphoma across the range of doses examined. The single agent MTD has not been determined and dose escalation continues. Updated safety and efficacy data from pts with lymphoma enrolled in dose escalation or ECs evaluating 25 mg BID and a higher dose (< MTD) of IPI-145 will be presented. Clinical trial information: NCT01476657.

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