Fractionated dose radiolabeled anti−prostate specific membrane antigen (PSMA) radioimmunotherapy (177Lu−J591) for progressive metastatic castration−resistant prostate cancer (mCRPC).

205 Background: Phase I and II single dose 177Lu−J591 studies have been published. Based on the theoretical advantages of dose fractionation on safety and efficacy, we initiated a phase I dose−escalation study of fractionated−dose 177Lu−J591. Methods: Men with progressive mCRPC with normal neutrophil and platelet counts were enrolled. The initial portion was 3+3 dose−escalation, with 6 cohorts of 3−6 patients receiving 2 doses 177Lu−J591, 2 weeks apart starting with 20 mCi/m2, escalating to 45 mCi/m2. After determining maximum tolerated dose (MTD), patients enrolled in 2 expansion cohorts at recommended phase II doses (RP2D). Planar imaging of 177Lu−J591 at 6−8 days following the initial dose was performed. Pre− and post−treatment PSA was measured for all patients and the highest dose−level cohorts had CTC counts (CellSearch) measured before and after treatment. Results: 48 patients enrolled with median age 74 (55−95) ), median baseline PSA 45.38 (1.93−766.5), 37.5% with prior chemo. The RP2D’s of fractionated 177Lu−J591 were 40 mCi/m2 or 45 mCi/m2 x2 with option for GCSF. Overall PSA decline ≥ 50% in 9 (18.8%), ≥ 30% in 14 (29.2%) and any PSA decline in 26 (54.2%); at RP2D doses (n = 32), 8 (25%) with ≥ 50%, 12 (37.5%) with ≥ 30%, and 20 (62.5%) with any PSA decline. Of 25 with available CTC counts, 14 declined, 8 remained stably favorable, and 3 increased. Of 12 with unfavorable baseline CTC counts, 8 (66.7%) became favorable at follow up, 2 decreased by 30% and 88% but remained ≥ 5, and 2 increased; 1 converted from < 5 to ≥ 5. Thirty-five (72.9%) had grade 3/4 hematological toxicities; 19 (59.4%) with Gr 4 heme toxicity in RP2D cohorts, with 15 (16.9%) receiving at least 1 platelet transfusion, 6 receiving GCSF, and 0 with febrile neutropenia. Overall 4 had Gr 1 transaminitis and 14 (29.2%) had grade 1 infusion reactions (without pre−medication). Accurate targeting of 177Lu−J591 at known sites of disease seen in 84.4%. Conclusions: Fractionated 177Lu−J591 is well tolerated with predictable, reversible myelosuppression, achieving a higher cumulative dose than possible with a single dose. Both PSA and CTC count control was achieved. Clinical trial information: NCT00538668.

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Fractionated dose radiolabeled antiprostate specific membrane antigen (PSMA) radioimmunotherapy (177Lu-J591) with or without docetaxel for metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.194 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 194-194

Author(s):

Jaspreet S Batra ◽

Beerinder S Karir ◽

Shankar Vallabhajosula ◽

Paul J. Christos ◽

Gillian Hodes ◽

...

Keyword(s):

Single Dose ◽

Phase I ◽

Phase Ii ◽

Dose Escalation ◽

Single Agent ◽

Maximum Tolerated Dose ◽

Dose Fractionation ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Higher Doses

194 Background: A phase II trial single-dose 177Lu-J591 was published. Dose fractionation offers theoretic advantages and 2 phase I dose-escalation studies of 177Lu-J591 have been performed to test the hypothesis that higher cumulative radiation doses can be administered with an acceptable toxicity profile. Methods: Pts with mCRPC and normal neutrophil and platelet counts were enrolled in 2 sequential phase I dose-escalation studies: (1) 177Lu-J591 administered as a single-agent 2 doses 2-weeks apart to determine the maximum tolerated dose (MTD) with expansion cohorts at the recommend phase II doses (RP2D) and (2) fractionated dose 177Lu-J591 in combination with docetaxel 75 mg/m2q3 weeks to determine the MTD. Results: 44 men with median age 75.4 (range 55.1-95.2) were enrolled in the single-agent fractionated dose escalation 177Lu-J591 trial and 15 men with median age 69.1 (49.3-80.8) were enrolled in 177Lu-J591 + docetaxel trial. The RP2D’s of fractionated 177Lu-J591 were 40 mCi/m2 x2 or 45 mCi/m2 x2 with the option for GCSF; at these doses (n=28), 8 (28.6%) with >50%, 11 (39.3%) >30%, and 16 (57%) of 28 pts with any PSA decline; pts at RP2D lived longer (p<0.0001). Predictable, reversible myelosuppression was seen. 18 (40.9%) received chemo prior to RIT and 24 (54.5%) received chemo post 177Lu-J591 [median of 7 cycles (range 1-20)]. In combination with docetaxel, the MTD/RP2D of 177Lu-J591 is 40 mCi/m2x2 doses (delivered with cycle 3), with 73.3% >50%, 80.0% >30%, and 86.7% with any PSA decline. Conclusions: Fractionated 177Lu-J591 is tolerated with subsequent PSA declines and reversible myelosuppression. The apparent dose-response of single-dose 177Lu-J591 appears confirmed with fractionated dosing (improved PSA declines and OS at higher doses). Despite predictable myelosuppression, chemotherapy is able to be delivered prior to 177Lu-J591, concurrently, or following radioimmuotherapy. Clinical trial information: NCT00538668 , NCT00916123 .[Table: see text]

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A phase I dose escalation study of PCUR-101 in men with metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16517 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16517-e16517 ◽

Cited By ~ 2

Author(s):

Christos Kyriakopoulos ◽

Channing Judith Paller ◽

Ajit Verma ◽

Karim Kader ◽

Jeff Kittrelle ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Human Study ◽

Study Drug ◽

Maximum Tolerated Dose ◽

Drug Formulation ◽

Clinical Activity ◽

Second Phase ◽

Castration Resistant Prostate Cancer ◽

Dose Escalation Study

e16517 Background: The combination of PCUR-101 (a synthetic form of the plant-derived medicinal agent, plumbagin) and surgical castration caused regression of androgen dependent tumors in mice. These promising pre-clinical results led to this first-in-human study of PCUR-101 in combination with androgen deprivation therapy (ADT) in men with metastatic, castrate resistant PCa (mCRPC). Methods: The goal of this phase I multicenter trial was to determine the safety profile, maximum tolerated dose (MTD), recommended phase II dose, clinical activity, and pharmacokinetic (PK) parameters of PCUR-101. A 3 + 3 dose escalation design was employed. Patients (pts) in cohorts of 3 were treated with escalating doses of PCUR-101 (50 mg – 200 mg) orally once daily continuously. Cycles were 28 days. Exploratory correlates of IL-6 and urine polyamines were also included. Results: 12 pts (median age 75 [range 63-86]) with mCRPC on ADT were treated in the dose escalation cohorts. No DLTs were observed during treatment and the MTD was not reached. The most frequent adverse events (AEs) included diarrhea (11 pts; all grade 1 or 2), nausea (7 pts; all grade 1 or 2), vomiting (4 pts; all grade 1 or 2) and constipation (3 pts; all grade 1 or 2). No objective responses were observed but 1 pt had PSA decrease by > 50%. Pts remained on study treatment for a median of 10 weeks (range 3-32 weeks). 5 pts, with stable disease, remain on active treatment. PK data could not be fully evaluated due to issues with the PK assay. Analyses of IL-6 and putrescine levels in pt samples indicate that, as compared to no treatment, PCUR-101 treatment in each cycle was associated with decreases in their levels. Reasons for treatment discontinuation included disease progression (n = 4), adverse event (n = 1; nausea and vomiting), subject withdrawal (n = 1), and investigator or sponsor decision (n = 1). After treating 12 pts, the sponsor decided to stop the trial in order to reformulate the study drug to allow for higher dosing and to redevelop the PK assay. Conclusions: At the doses evaluated, PCUR-101 combined with ADT was seen to be safe and may prolong disease stability in men with mCRPC. A second phase I study is planned using a new drug formulation and PK assay. Clinical trial information: NCT03137758.

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Phase I study of tomuzotuximab, a glycoengineered therapeutic antibody against the epidermal growth factor receptor, in patients with advanced carcinomas

ESMO Open ◽

10.1136/esmoopen-2017-000303 ◽

2018 ◽

Vol 3 (2) ◽

pp. e000303 ◽

Cited By ~ 7

Author(s):

Walter Fiedler ◽

Sara Cresta ◽

Henning Schulze-Bergkamen ◽

Sara De Dosso ◽

Jens Weidmann ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Phase I ◽

Dose Escalation ◽

Antitumour Activity ◽

Growth Factor Receptor ◽

Maximum Tolerated Dose ◽

Dose Escalation Study ◽

Epidermal Growth

BackgroundChanges in glycosylation of the constant domain (Fc) of monoclonal antibodies (mAbs) enhance antibody-dependent cell-mediated cytotoxicity independently of downstream effects following receptor blockade by the antibody, thus extending their indication. We investigated the safety, pharmacokinetics, pharmacodynamics and antitumour activity of tomuzotuximab, an IgG1 glycoengineered mAb against the epidermal growth factor receptor with enhanced tumour cytotoxicity in a phase I dose-escalation study (NTC01222637).Patients and methodsForty-one patients with advanced solid tumours refractory to standard therapies received tomuzotuximab weekly (12–1370 mg) or two-weekly (990 mg) on a three-plus-three dose escalation design.ResultsA maximum tolerated dose was not reached. The most frequent treatment-related adverse events were infusion-related reactions in 31 (76%) patients (grade 3, 12%), mainly confined to the first dose, and skin toxicities (grade 1 or 2) in 30 (73%) patients. Hypomagnesaemia was observed in 9 out of 23 evaluable patients (39%). Similar to cetuximab, tomuzotuximab concentrations increased proportionally to dose from doses≥480 mg with a median terminal half life (t½) of 82 hours, range 55–113 hours. Antitumour activity included one complete response ongoing since more than 4.5 years in a patient with non-small-cell lung cancer and one partial response lasting 353 days in a patient with colorectal cancer. Twelve patients achieved stable disease (median, 166 days, range, 71–414 days) and two patients had prolonged control (>1 year) of their non-measurable disease.ConclusionTomuzotuximab was safe and showed promising antitumour activity in heavily pretreated patients with advanced metastatic disease. A phase IIb trial of chemotherapy and weekly tomuzotuximab or cetuximab followed with maintenance therapy with the corresponding mAb in patients with recurrent or metastatic head and neck squamous cell carcinoma is ongoing.

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SAFETY AND TOLERABILITY OF GLIAL GROWTH FACTOR 2 IN PATIENTS WITH CHRONIC HEART FAILURE: A PHASE I SINGLE DOSE ESCALATION STUDY

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(13)60707-x ◽

2013 ◽

Vol 61 (10) ◽

pp. E707 ◽

Cited By ~ 7

Author(s):

Daniel J. Lenihan ◽

Sarah Anderson ◽

Carrie Geisberg ◽

Anthony Caggiano ◽

Andrew Eisen ◽

...

Keyword(s):

Heart Failure ◽

Single Dose ◽

Growth Factor ◽

Chronic Heart Failure ◽

Phase I ◽

Dose Escalation ◽

Dose Escalation Study ◽

Glial Growth Factor

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Phase I study of ABT-751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab in patients with advanced colorectal cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13553 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13553-13553

Author(s):

W. A. Messersmith ◽

M. A. Rudek ◽

D. Laheru ◽

M. Zhao ◽

P. He ◽

...

Keyword(s):

Colorectal Cancer ◽

Combination Therapy ◽

Phase I ◽

Dose Level ◽

Dose Escalation ◽

Advanced Colorectal Cancer ◽

Standard Of Care ◽

Maximum Tolerated Dose ◽

Total Daily Dose ◽

Dose Escalation Study

13553 Background: ABT-751 (A) is an orally (PO) bioavailable sulfonamide with antimitotic properties. We are performing a non-randomized phase I/II dose-escalation study of A in combination with capecitabine (C), irinotecan (I) and bevacizumab (B) to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) in patients with advanced colorectal cancer (1st or 2nd line). Methods: Patients are treated with A QD for 7d (lead-in) and then begin 21-d cycles of treatment with A (QD) and C (BID) d1–14 PO, I d1 IV, and B d1 IV. Dose escalation started at dose level (DL) 1 at A 150 mg, I 200 mg/m2, and C 1600 mg/m2 (total daily dose) and escalated to full dose CAPIRI (I 250 mg/m2, and C 2000 mg/m2) for DL2. B was then added as standard of care at 7.5 mg/kg for DL2b (and later, DL1b). Blood samples were collected for pharmacogenomics (PG), pharmacodynamics (PD), steady-state PK of A and A metabolites when administered alone or in combination with C, I, and B, and PK of I and I metabolites. Serial dynamic contrast MRI’s, before and after the ABT-751 monotherapy lead-in period, are being performed in a subset of subjects. Results: Eight patients have been treated at dose levels 1 (3), 2 (2), and 2b (3). One patient on DL2 experienced g3 transaminitis and another on DL2b had F&N which were dose-limiting. Dose level 1 is being expanded to 6 patients, now with B (DL1b). Other g3/4 toxicities have included g4 neutropenia (1 subject DL2, 1 DL2b). The formation of A glucuronide appears decreased during combination therapy (see table). I PK, PD, and PG samples were collected and analysis is pending. Of 8 subjects, there have been 4 PD and 4 SD after 2 cycles. Conclusions: The combination therapy of A 150 mg and 20% dose-reduced CAPIRI appears well-tolerated. Patient accrual continues at DL1b. [Table: see text] No significant financial relationships to disclose.

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A phase I dose escalation study of pemetrexed in patients with advanced head and neck squamous cell cancer (HNSCC)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.6055 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 6055-6055 ◽

Cited By ~ 1

Author(s):

P. H. Morrow ◽

B. S. Glisson ◽

L. E. Ginsberg ◽

S. M. Lippman ◽

M. S. Kies ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Cell Cancer ◽

Maximum Tolerated Dose ◽

Vitamin Supplementation ◽

Dose Escalation Study ◽

Grade 3 ◽

Ecog Ps ◽

Dose Levels ◽

Neck Squamous Cell Cancer

6055 Background: Despite recent advances in therapy, patients (pts) with recurrent or metastatic HNSCC continue to demonstrate a poor median survival. In these pts, early trials with pemetrexed, a novel antimetabolite that acts upon several enzymes involved in pyrimidine and purine synthesis, have demonstrated promising efficacy and tolerability. Prior studies found that the administration of oral dexamethasone with pemetrexed reduced the incidence of skin rash. Later, vitamin supplementation (B12 and folic acid), given in addition to the dexamethasone, further diminished side effects. However, no trial has yet evaluated the appropriate steroid dose and its relation to the dosing of pemetrexed, in the setting of vitamin supplementation. We conducted a phase I trial to determine the maximum tolerated dose, toxicity, and preliminary efficacy of pemetrexed when given with different schedules of, or in the absence of, dexamethasone in pts with advanced HNSCC who had been treated with at least one or more chemotherapy regimens. Methods: Eligible pts had metastatic or recurrent HNSCC, prior treatment with one or more chemotherapy regimens, ECOG PS =2, and life expectancy >3 months. A conventional algorithm-based dose escalation design was applied, with three predefined dose levels (DL) of pemetrexed (500 mg/m2, 600 mg/m2, and 700 mg/m2) within each schedule of dexamethasone (none, 20 mg IV on day 1, and 4 mg orally bid for 3 days). Results: A total of 23 pts have been enrolled; 18 pts were evaluable. Median age was 57 years (range 47–82). Median ECOG PS was 1 (range 0–2), and 75% of pts were male. Number of prior chemotherapy regimens were as follows: 1 (40%), 2 (35%), 3 (15%), and 4 (10%). Preliminary data demonstrated only 2 treatment-related adverse events that were grade 3 or greater: anemia (DL1) and pneumonia (DL 1). In all, 13 pts have received pemetrexed with less than standard recommended dexamethasone dosing (none or IV), including 7 pts who received no dexamethasone. Of the 18 evaluable pts, 1 pt had a partial response and 2 pts had stable disease. Conclusions: This represents the first study that demonstrates that steroids may not be required as premedication with pemetrexed. Due to the limited toxicity observed, trial enrollment continues with dose escalation. [Table: see text]

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A first-in-human phase I study to evaluate the fully human monoclonal antibody OMP-59R5 (anti-Notch2/3) administered intravenously to patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3025 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3025-3025 ◽

Cited By ~ 1

Author(s):

Anthony W. Tolcher ◽

Rashmi Chugh ◽

Glenda Chambers ◽

Villette Thorpe ◽

Jakob Dupont ◽

...

Keyword(s):

Tumor Growth ◽

Phase I ◽

Dose Escalation ◽

Human Monoclonal Antibody ◽

Notch Pathway ◽

Maximum Tolerated Dose ◽

Dose Escalation Study ◽

Stem And Progenitor Cells ◽

Grade 3 ◽

Cancer Agent

3025 Background: The Notch pathway plays a central role in embryonic development, the regulation of stem and progenitor cells, and is implicated centrally in many human cancers. OMP-59R5 is a fully human IgG2 originally identified by binding to Notch2. It inhibits the signaling of both Notch2 and Notch3 receptors. Mouse xenograft studies using minimally-passaged, patient-derived xenografts show that OMP-59R5 impedes tumor growth and eliminates cancer stem cells (CSCs) in many tumor types. OMP-59R5 modulates the expression of stromal genes and genes associated with the function of tumor vascular pericytes. As such, OMP-59R5 is a novel anti-cancer agent that inhibits tumor growth through direct actions on tumor cells, including CSCs, and effects the stroma and vasculature. Methods: A phase I dose escalation study (3+3 design) was initiated in solid tumor patients. OMP-59R5 was administered to study safety, pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy, and to determine the maximum tolerated dose (MTD). Results: Twenty-four patients have been enrolled in 5 dose-escalation cohorts at doses of 0.5, 1, 2.5, and 5mg/kg administered weekly (QW) and 5mg/kg administered every other week (QOW). The most frequently reported drug-related adverse events were: mild to moderate diarrhea, fatigue, nausea, vomiting, decreased appetite, and constipation. Diarrhea was dose related and occurred at doses ≥2.5mg/kg weekly and appears less pronounced with every other week dosing. Two dose-limiting toxicities (grade 3 diarrhea and grade 3 hypokalemia) occurred at 5mg/kg QW and 2.5mg/kg was established as an MTD for QW dosing. A QOW dosing schedule is currently under investigation. The PK of OMP-59R5 was characterized by fast and dose-dependent clearance. Two patients (Kaposi’s sarcoma at 5mg/kg and adenoid cystic carcinoma at 2.5mg/kg) had prolonged stable disease for ≥110 days. PD analyses for Notch pathway modulation are ongoing. Conclusions: OMP-59R5 is generally well tolerated. An MTD of 2.5mg/kg QW has been established and a QOW schedule is currently under study. Updated results will be presented.

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