scholarly journals Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study

2018 ◽  
Vol 36 (4) ◽  
pp. 391-398 ◽  
Author(s):  
Margaret K. Callahan ◽  
Harriet Kluger ◽  
Michael A. Postow ◽  
Neil H. Segal ◽  
Alexander Lesokhin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Dose Escalation ◽  
Objective Response ◽  
Safety Data ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Grade 3

Purpose The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-year overall survival (OS). Patients and Methods Concurrent cohorts 1, 2, 2a, and 3 received escalating doses of NIVO plus IPI once every 3 weeks for four doses, followed by NIVO once every 3 weeks for four doses, then NIVO plus IPI once every 12 weeks for eight doses. An expansion cohort (cohort 8) received concurrent NIVO 1 mg/kg plus IPI 3 mg/kg once every 3 weeks for four doses, followed by NIVO 3 mg/kg once every 2 weeks, which is the dose and schedule used in phase II and III studies and now approved for patients with unresectable or metastatic melanoma. Results Among all concurrent cohorts (N = 94) at a follow-up of 30.3 to 55.0 months, the 3-year OS rate was 63% and median OS had not been reached. Objective response rate by modified WHO criteria was 42%, and median duration of response was 22.3 months. Incidence of grade 3 and 4 treatment-related adverse events was 59%. The most common grade 3 and 4 treatment-related adverse events were increases in lipase (15%), alanine aminotransferase (12%), and aspartate aminotransferase (11%). One treatment-related death (1.1%) occurred in a patient who had multiorgan failure 70 days after the last dose of NIVO plus IPI. Conclusion This is the longest follow-up for NIVO plus IPI combination therapy in patients with advanced melanoma. The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma.

Clinical activity of fianlimab (REGN3767), a human anti-LAG-3 monoclonal antibody, combined with cemiplimab (anti-PD-1) in patients (pts) with advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9515-9515
Author(s):  
Omid Hamid ◽  
Ding Wang ◽  
Tae Min Kim ◽  
Sang-We Kim ◽  
Nehal J. Lakhani ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Adrenal Insufficiency ◽  
Safety Profile ◽  
Phase 1 ◽  
Objective Response ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Treatment Naïve ◽  
Grade 3

9515 Background: Fianlimab and cemiplimab are two high-affinity, fully human, hinge-stabilized IgG4 monoclonal antibodies. In a Phase 1 dose escalation study, fianlimab combined with cemiplimab showed an acceptable safety profile and some clinical activity in pts with advanced malignancies. Here, we present safety and clinical activity data from two expansion cohorts of pts with advanced melanoma (anti–programmed cell death/ligand-1 [anti–PD-(L)1] naïve or experienced) who were treated with fianlimab + cemiplimab and had an opportunity for first on-treatment tumor assessment (cut-off date: Jan 4, 2021). Methods: Pts with advanced melanoma who had no prior anti–PD-(L)1 treatment (naïve) or prior anti–PD-(L)1 treatment within 3 months of screening (experienced) received fianlimab 1600 mg + cemiplimab 350 mg by IV infusion every 3 weeks. Tumor measurements were performed every 6 weeks for the first 24 weeks and subsequently every 9 weeks per RECIST v1.1. Results: 48 pts with advanced melanoma were treated with the combination therapy: 33 were anti–PD-(L)1 naïve and 15 were anti–PD-(L)1 experienced (median age: 69 years vs 59 years; male: 66.7% vs 46.7%; Caucasian: 87.9% vs 60%). The safety profile (including immune-related adverse events [AEs]) of fianlimab + cemiplimab combination therapy was similar to that of anti–PD-1 monotherapy with one exception. The rate of adrenal insufficiency, 8.3% (4/48) of pts, is similar to the rate previously observed with anti–PD-1 + anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) combination therapy but higher than that observed with anti–PD-1 monotherapy. Grade ≥3 treatment-emergent AEs (TEAEs) occurred in 35.4% (17/48) of patients; Grade ≥3 serious TEAEs occurred in 22.9% (11/48) of patients; 8.3% (4/48) of patients discontinued treatment due to a TEAE. The most common TEAEs were fatigue (n = 15, 31.3%) and rash (n = 11, 22.9%). By investigator assessment, objective response rate (includes unconfirmed complete [CR] and partial responses [PR]) was 63.6% (3 CRs and 18 PRs) for anti–PD-(L)1 naïve pts and 13.3% (1 CR and 1 PR) for anti–PD-(L)1 experienced pts. Median progression-free survival and median duration of response for the anti–PD-(L)1 treatment naïve cohort have not been reached. Prognostic clinical markers and tumor biomarkers such as expression of LAG-3, PD-L1, and major histocompatibility complex II are being evaluated. Recruitment is ongoing. Conclusions: The safety profile of fianlimab + cemiplimab is similar to that observed with cemiplimab monotherapy and other anti–PD-1s, with the exception of higher rate of adrenal insufficiency. Fianlimab + cemiplimab combination has shown clinical activity for pts with advanced melanoma that is similar to anti–PD-1 + CTLA-4 combination therapy, but with lower demonstrated rates of TEAEs. Clinical trial information: NCT03005782.

Clinical Activity of the Immunoconjugate CMC-544 in B-Cell Malignancies: Preliminary Report of the Expanded Maximum Tolerated Dose (MTD) Cohort of a Phase 1 Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2711-2711 ◽  
Author(s):  
Luis Fayad ◽  
Hemant Patel ◽  
Gregor Verhoef ◽  
Myron Czuczman ◽  
James Foran ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Remission Rate ◽  
International Workshop ◽  
Phase 1 ◽  
Objective Response ◽  
Safety Data ◽  
Clinical Activity ◽  
B Cell Lymphomas ◽  
Grade 3

Abstract Introduction: CMC-544 is an antibody-targeted chemotherapy agent composed of a humanized antibody that specifically targets the CD22 antigen, conjugated to calicheamicin, a potent cytotoxic antitumor agent. Malignant cells of mature B-lymphocyte lineage express CD22, suggesting that CMC-544 may be useful for treating lymphomas of B-cell origin. A phase 1 dose-escalation trial of CMC-544 was performed at 14 European and US sites with 36 patients in the dose escalation portion and 48 in the expanded MTD portion. The MTD dose was 1.8 mg/m2 every 4 weeks. In the dose escalation phase the main toxicities observed were thrombocytopenia, asthenia, nausea, neutropenia, elevated liver function tests (LFTs) and anorexia. Grade 3–4 levels were only seen for thrombocytopenia, asthenia, neutropenia and LFTs (incidence of 40%, 13%, 9% and 9% respectively). Responses were seen in 8/22 (36%) patients (Advani A, et. al. Blood, abstract# 230, 2005:106). We now report the results of the expanded cohort at the MTD. Patients and Methods: Relapsed/refractory lymphoma patients were treated at the 1.8 mg/m2 dose level every 4 weeks. In addition to safety data, preliminary efficacy data (assessed using the International Workshop to Standardize Response Criteria for NHL) were collected. Results: As of July 2006, 48 patients were treated: median age 57 years (range 26–75); 51% females; 61% with ≥ 4 prior lines of therapy; 22 (46%) follicular lymphomas (FL) and 26 (54%) diffuse large B-cell lymphomas (DLBCL). Data were available on 48 patients evaluable for safety and 34 patients (19 FL and 15 DLBCL) evaluable for response. The overall safety profile was manageable; the most common drug-related adverse events (all grades) included thrombocytopenia (90%; the only bleeding noted was grade 1–2 epistaxis [12%]), asthenia (57%), nausea (39%), neutropenia (37%) and elevated levels of AST/SGOT (41%), ALT/SGPT (18%), alkaline phosphatase (27%) and bilirubin (18%). Grade 3–4 AEs that occurred with a frequency ≥ 10% included thrombocytopenia (57%) and neutropenia (29%). Responses in evaluable patients are shown in Table 1. The objective response rate was 69% and 33% for patients with FL and DLBCL, respectively. Conclusions: CMC-544 exhibits effficacy against recurrent/refractory B-cell lymphomas, with the main toxicity being clinically manageable, self limited thrombocytopenia. These encouraging data support the continuing development of CMC-544. Number (%) of Responses in Evaluable Patients: Response Follicular Lymphoma (n=19) DLBCL (n=15) ORR = Overall Remission Rate, (CR/CRu+PR) CR/CRu 6 (31.7) 2 (13.3) PR 7 (36.8) 3 (20.0) ORR 13 (68.5) 5 (33.3)

Initial results from a phase I, open-label, dose escalation study of the oral BRAF inhibitor LGX818 in patients with BRAF V600 mutant advanced or metastatic melanoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9028-9028 ◽  
Author(s):  
Reinhard Dummer ◽  
Caroline Robert ◽  
Marta Nyakas ◽  
Grant A. McArthur ◽  
Ragini Reiney Kudchadkar ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Plasma Concentrations ◽  
Braf Inhibitor ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Open Label ◽  
Dose Escalation Study ◽  
Pretreated Patients ◽  
Initial Results

9028 Background: LGX818, a potent and selective BRAF inhibitor (BRAFi) being investigated in BRAF V600 mutant melanoma, has unique biochemical properties with a dissociation half-time > 10 times longer than other BRAF inhibitors. Methods: A phase I trial of LGX818 administered orally once (qd) or twice (bid) daily in BRAF V600 tumors was initiated to define the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and to assess pharmacokinetics and clinical activity in BRAFi–naive or pretreated patients with BRAF V600 mutant advanced melanoma. Baseline assessment of biomarkers from MAPK/PI3K pathways and pharmacodynamics were also evaluated. Results: Fifty-four patients have been enrolled in the dose-escalation phase (dose levels [DLs], 50-700 mg qd [n=42] and 75-150 mg bid [n=12]). LGX818 plasma concentrations increased proportionally by dose with a mean t1/2 of 4 hours and steady state in ≈ 15 days. The MTD/RP2D (450 mg qd) was well tolerated. Seven patients had a dose limiting toxicity (DLT): 5 at qd (1 each with hand-foot skin reaction [HFSR], foot pain, fatigue, diarrhea/rash, insomnia/asthenia) and 2 at bid (1 facial paresis/confusion, 1 musculoskeletal pain/neuralgia). All DLTs were grade 3 and reversible. The most common adverse events (≥ 20%) suspected to be treatment related were cutaneous (rash, dry skin, HFSR, pruritus, keratosis pilaris, alopecia), pain in extremity, arthralgia, and fatigue. Squamous cell carcinoma was observed in 2 patients (1 naive and 1 pretreated). As of 30 Sept 2012, the preliminary efficacy (all DLs) in patients with at least 1 postbaseline tumor assessment was 16 partial responses [PRs] (67%; 12 confirmed) out of 24 BRAFi–naive patients and 2 PRs (8.3%; 1 confirmed) among 24 BRAFi–pretreated patients. Responses were seen at all DLs from 50 to 550 mg qd. Updated safety and efficacy including time to event endpoints will be reported. Conclusions: Initial results from this study identified the MTD/RP2D as 450 mg/day and provided an early sign of promising activity in advanced melanoma. Expansion cohorts are ongoing in BRAFi–naive and BRAFi–pretreated melanoma and colorectal cancer. Clinical trial information: NCT01436656.

Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9533-9533 ◽  
Author(s):  
Michael B. Atkins ◽  
John M. Kirkwood ◽  
Jedd D. Wolchok ◽  
Margaret K. Callahan ◽  
Harriet M. Kluger ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Performance Status ◽  
Study Drug ◽  
Advanced Melanoma ◽  
Post Treatment ◽  
Dose Escalation Study ◽  
Term Survival

9533 Background: We previously reported a 3-year overall survival (OS) rate of 63% with NIVO+IPI concurrent therapy in the initial phase I dose-escalation study for the combination, conducted in patients (pts) with advanced melanoma. Here, we report OS after 5 years of overall study follow-up and assess survival rates after stopping treatment. Methods: Adults with previously treated or untreated unresectable stage III or IV melanoma, and ECOG performance status of 0 or 1, received NIVO + IPI Q3W × 4 as mg/kg in one of the following cohorts: (1) NIVO 0.3 + IPI 3; (2) NIVO 1 + IPI 3; (2a) NIVO 3 + IPI 1; (3) NIVO 3 + IPI 3; (8) NIVO 1 + IPI 3. Cohorts 1-3 received maintenance with NIVO Q3W × 4, then NIVO + IPI Q12W × 8 at assigned doses; cohort 8 received NIVO Q2W for up to 96 weeks. Patients were followed for the primary endpoint of safety and the secondary endpoints of response and progression-free survival for up to 2.5 years, then for the survival exploratory endpoint for up to an additional 3 years, for a maximum study participation of 5.5 years. Results: At a median follow-up of 43.1 months (range 0.9-76.7) in all cohorts (N = 94), the 4- and 4.5-year OS rates were both 57% (95% CI: 47, 67). The 4-year OS rates for pts with normal (n = 58) versus elevated LDH (n = 36) were 62% (48, 74) versus 49% (32, 65); for pts with wild-type (n = 66) and mutant (n = 24) BRAF tumors, 4-year OS rates were 54% (41, 65) and 61% (38, 77), respectively. Following the last dose of study drug (for any reason), overall post-treatment 1-, 2-, and 3-year OS rates were 74% (64, 82), 65% (55, 74), and 56% (46, 66), respectively; in pts who discontinued due to study drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84% (66, 93), 75% (55, 86), and 65% (45, 79), respectively, and in pts who discontinued for disease progression (n = 30), these were 52% (33, 68), 34% (18, 51), and 24% (11, 41), respectively. Conclusions: This updated analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma. Clinical trial information: NCT01024231.

Phase I Dose Escalation Study of Flavopiridol in Combination with Fludarabine and Rituximab: Activity in Indolent B-Cell Lymphoproliferative Disorders and Mantle Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2492-2492
Author(s):  
Thomas S. Lin ◽  
Beth Fischer ◽  
Mollie E. Moran ◽  
David M. Lucas ◽  
Roshini S. Shank ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Lymphoproliferative Disorders ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Mantle Cell ◽  
Grade 3

Abstract The cyclin-dependent kinase inhibitor flavopiridol was inactive when administered as a 72-hour infusion, but a 1-hr IV bolus dosing schedule demonstrated clinical activity in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Flavopiridol induces apoptosis via a p53-independent mechanism. Thus, we hypothesized that flavopiridol may eliminate tumor cells resistant to fludarabine and rituximab. We report preliminary results of an ongoing phase I dose escalation study of flavopiridol in combination with fludarabine and rituximab in patients (pts) with MCL, CLL and other indolent B-cell lymphoproliferative disorders. Pts had adequate marrow function (ANC ≥ 1500, hemoglobin ≥ 9.0, platelets ≥ 100,000), organ function, and performance status (ECOG 0–2) and provided informed consent. Pts in all cohorts received fludarabine 25 mg/m2 IV on days 1–5 and rituximab 375 mg/m2 on day 1 of each 28-day cycle. The planned dose escalation of flavopiridol was 50 mg/m2 by 1-hr IV bolus on day 1 (cohort 1), days 1–2 (cohort 2), or days 1–3 (cohort 3) of each cycle. Treatment was for up to 6 cycles, and pts were placed on prophylactic Bactrim and Valtrex. Fifteen pts have been enrolled to date, and 9 pts are evaluable for toxicity and response. Median age of these 9 pts was 67 years (range, 43–72), and 4 pts were male. Pts had the following diagnoses: CLL (5), MCL (2) and follicular lymphoma (FL; 2). Four pts had received 1–2 prior therapies; 5 pts were previously untreated. CLL pts had Rai stage III/IV disease (2) or required treatment for Rai stage I/II disease (3) by NCI 96 criteria. MCL/FL pts were stage III/IV (3) or had progressive stage II disease (1). Three pts were treated in cohort 1; 2 pts completed 6 cycles, but 1 pt was removed from study after cycle 3 due to prolonged cytopenias. Six pts were treated in cohort 2. Two pts developed dose-limiting toxicity; 1 pt developed grade 3 confusion and grade 3 generalized seizures during cycle 2, and 1 pt developed nausea and diarrhea, which resulted in grade 3 acute renal failure. Infectious toxicity was limited to 1 pt who was hospitalized for 48 hrs with a grade 3 upper respiratory infection and febrile neutropenia. Three pts in cohort 2 were removed from study for prolonged cytopenias after 3, 3 and 4 cycles; only 1 pt in cohort 2 completed 6 cycles. Two of the 6 pts in cohort 2 did not receive flavopiridol after cycles 2 and 3, due to life threatening tumor lysis in our single agent flavopiridol study. Response was graded by NCI 96 criteria (CLL) or IWG criteria (MCL/FL). Overall response rate (ORR) was 100%; 7 pts (78%) achieved CR, and 2 pts achieved PR (22%). Two pts relapsed after 7 and 8 months; 7 pts remain in remission a median of 9 (range,7–12) months after therapy. Of note, all 4 MCL/FL pts remain in CR. An ongoing expansion of 12 pts at the cohort 1 dose level is being conducted, to better define toxicity and efficacy; 6 pts have been enrolled to date. In conclusion, flavopiridol, fludarabine and rituximab exhibited significant clinical activity in a small group of pts, with a 78% CR rate. This combination warrants further study, particularly with consideration to an altered flavopiridol schedule using our highly active 30-minute bolus followed by 4-hour infusion regimen.

Oral Forodesine (Bcx-1777) Is Clinically Active in Refractory Cutaneous T-Cell Lymphoma: Results of a Phase I/II Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2467-2467 ◽  
Author(s):  
Madeleine Duvic ◽  
Andres Forero-Torres ◽  
Francine Foss ◽  
Elsie A. Olsen ◽  
Youn Kim
Keyword(s):  
T Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Objective Response ◽  
Safety Data ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Cutaneous T Cell Lymphoma ◽  
Percent Change

Abstract Background: Forodesine is a potent, rationally designed purine nucleoside phosphorylase (PNP) inhibitor that is orally bioavailable. IV forodesine has shown clinical activity in patients with cutaneous T-cell lymphoma (CTCL). The objective of this phase I/II study was to evaluate the safety, PK profile, and efficacy of oral forodesine in patients with refractory CTCL. Methods: An open-label dose-escalation study of fordesine, 40 to 320 mg/m2 qd for 4 weeks, was undertaken to evaluate the safety and PK profile of oral forodesine, followed by an investigation of the expansion of the optimal biologic dose (dose with maximum PNP inhibition and elevation of plasma deoxyguanosine levels) to assess efficacy. Previously treated, refractory CTCL patients with stage IB or greater disease were eligible for participation. The primary end point was objective response (OR) = complete response [CR] plus partial response [PR], as measured by the severity-weighted assessment tool (SWAT; see Figure) and physicians’ global assessment (PGA) Results: Overall, 37 patients were treated, including 14 patients in the dose-escalation portion of the study. No dose-limiting toxicities were observed with target doses of ≤320 mg/m2; thus, a maximum tolerated dose was never defined. Based on PK/PD results, an 80 mg/m2 qd dose was identified as the optimal biologic dose, and this ongoing study was expanded to enroll a total of 28 patients (median age, 64 yr; range, 28–81 yr). The OR rate was 53.6% (15/28 patients; 2 [7.1%] with a CR and 13 [46.4%] with a PR). The proportion of patients with stage IIB or greater disease was 19/28 (67.9%). Response in this population was seen in 10 (52.6%) of the 19 patients (1 [5.3%] with a CR and 9 [47.4%] with a PR). The percent change in SWAT score from baseline as a function of time demonstrated a progressive decrease over a 24-week period. To-date, 12 (42.9%) of 28 patients have completed ≥4 months of treatment. Safety data were recorded for all 37 patients treated with forodesine. The most common adverse events classified as grade 2 or less, without regard to causality, were nausea (30%), dizziness (22%), pruritus (22%), fatigue (19%), headache (19%), peripheral edema (19%), and pyrexia (16%). The only adverse event classified as grade 3 or greater, without regard to causality, and occurring in at least two patients, was lymphopenia, which was observed in two patients (5%). Conclusions: Oral forodesine is effective in the treatment of refractory CTCL patients and has an encouraging safety profile. SWAT SCORE: Percent Change from Baseline SWAT SCORE: Percent Change from Baseline

A phase I trial of isolated hepatic perfusion (IHP) using 5-FU and oxaliplatin in patients with unresectable isolated liver metastases (ILM) from colorectal cancer (CRC).

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 283-283
Author(s):  
Deepa Magge ◽  
Amer H Zureikat ◽  
David L. Bartlett ◽  
Matthew Peter Holtzman ◽  
Haroon Choudry ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Systemic Exposure ◽  
Fixed Dose ◽  
Dose Escalation Study ◽  
Total Platinum ◽  
Isolated Hepatic Perfusion ◽  
Prospective Phase ◽  
Grade 3

283 Background: IHP is a proven approach for regional delivery of chemotherapy in patients with unresectable ILM. This study sought to determine safety and MTD of administering 5FU in combination with fixed dose oxaliplatin via IHP. Methods: Prospective Phase I dose escalation with standard 3x3 dosing. Subjects with unresectable ILM from CRC scheduled to receive an HAI pump were eligible. IHP employed fixed dose oxaliplatin (previously established)with escalating doses of 5FU. 1 endpoint was to determine MTD for this combination. 2 endpoints were response to IHP alone, PFS, and OS for IHP + HAI-FUDR. Systemic and IHP plasma PK of 5FU, anabolites, total, and free platinum were determined by validated assays. Results: Between Aug 2007 - Mar 2011, 11 subjects were enrolled. All patients received at least one line of pre-IHP systemic chemotherapy. There were 4 Grade 3 SAE (36.3%) and no grade 4 events. 2 DLTs occurred in the second dose cohort of 300mg/m2. Dose escalation was terminated and 200mg/m2 5FU was determined to be the MTD. There was 1 DLT in the dose de-escalating phase of 200mg/m2. At first follow-up, 9 pts (82%) had a partial response, while 2 (18%) had stable disease. 64% of pts had a >50% decrease in CEA level. Actuarial 1 and 2 year survival was 100% and 75% respectively, with median follow-up of 23 mos. IHP exposures (AUC0-60min) were 10.9±4.5 µgPt·h/mL (platinum), 49.3±30.7 µg·h/mL 5FU (DL1) and 70.5±35.5 µg·h/mL 5FU (DL2). Free platinum represented 82±14% of total platinum. Systemic exposure (AUC0-inf) relative to IHP exposure was negligible for both total platinum (1.1±1.5%) and 5FU (0.09±0.10%). IHP exposure to metabolites relative to 5FU was 4.9±2.5% for FUrd and 0.23±0.14% for FdUrd, respectively. Conclusions: MTD for IHP with 5FU and oxaliplatin is 200 mg/m2 and 40mg/m2 respectively. Systemic exposure to the agents was minimal. The response and survival observed in this dose escalation study warrants assessment in a larger phase II trial. [Table: see text]

A phase I open-label, dose-escalation study of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 323-323 ◽  
Author(s):  
Susan Joy Littman ◽  
Daniel Monti ◽  
Andrew Newberg ◽  
Anthony Bazzan ◽  
Madhavan V. Pillai ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Steady State ◽  
Phase I ◽  
Dose Escalation ◽  
Safety Data ◽  
Open Label ◽  
Dose Escalation Study ◽  
First Line Therapy ◽  
Grade 3 ◽  
Vit C

323 Background: IV ascorbic acid (vit c) is a prodrug for steady state formation of ascorbate radical (Asc·-) in the extracellular space resulting in sustained production of H2O2 leading to selective killing of tumor cells by a pro-oxidative mechanism. In preclinical models of panc cancer pharmacologic concentrations of Asc·- with gem resulted in a synergistic cytotoxic response. We conducted a Phase I dose escalation study of IV ascorbic acid with gem plus erlotinib chemo as first line therapy in panc cancer. Methods: Patients with adv panc cancer were enrolled using a standard 3+3+3 design to assess the safety and pharmacology of IV vit c in combo with gem and erlotinib. Cohort 1 received 50 g IV vit c and subsequent cohorts were escalated by 25 g to a final dose of 100 g. Pts were given 3 infusions of vit c per week on separate days for 8 w (1 cycle). IV gem was given on day 1 (1000 mg/m2) and weekly for 7 w followed by a rest week. Oral erlotinib (100 mg) was given daily for 8 w. Trt continued until disease progression or toxicity. Steady state ascorbate PK was assessed in cohorts 2 and 3. AEs were determined using NCI CTCAE v3.0. Tumor responses were assessed per RECIST. Results: Of 14 pts enrolled, 9 or 3 per cohort completed the study. Median age was 64 years. 5 pts did not complete trt (2 discontinued, 3 died). 9 pts completed at least 24 ascorbic acid trts and 1 cycle of gem/erlotinib therapy. There were 24 AEs. These included 15 non-serious AEs and 8 SAEs. The most frequent AEs were grade 1/2 thrombocytopenia. Other grade 1/2 events included anemia, hyperglycemia, abd discomfort, ascites and infection. SAEs: 2 grade 3 heme, 1 grade 3 GI, 1 grade 3 infectious and 2 grade 4 thrombosis. Plasma asc levels were 25.3 - 31.9 mm/L for pts receiving the 100g dose. 8 of the 9 pts had a reduction in the panc primary with 1 pt having no change at 8 w. For non-target lesions, 2 had PD and 7 had SD per RECIST. Conclusions: Overall safety data do not reveal AEs other than those expected in patients with metastatic panc cancer and/or treatment with gem and erlotinib. Addition of IV ascorbic acid did not increase toxicity. Preliminary efficacy results are encouraging. A phase II study is planned.

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 A Dose Escalation Study of RP6530, a Novel Dual PI3K δ/γ Inhibitor, in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3004-3004 ◽  
Author(s):  
Yasuhiro Oki ◽  
Auris Huen ◽  
Prajak J Barde ◽  
Kumar Penmetsa ◽  
Alda Ashu ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Performance Status ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Grade 3

Abstract Introduction: The δ isoform of PI3K is highly expressed in cells of hematopoietic origin. The γ isoform is associated with T-lymphocytes and neutrophils and plays a distinct role in T-cell function. Since δ/γ isoforms are synergistic in the growth and survival of certain T-cell malignancies, dual targeting of PI3K δ/γ is an attractive intervention strategy in patients with T-cell lymphoma. RP6530 is a novel, highly specific dual PI3K δ/γ inhibitor with nanomolar inhibitory potency for both isotypes. It has shown acceptable safety profile and efficacy in patients (pts) with advanced hematologic malignancies in a Phase 1 study (ASH 2015). Herein, we present the preliminary results from an ongoing Phase 1/1b, dose escalation study of RP6530 in 11 pts with mature T-cell neoplasms (NCT02567656). Methods: The study consists of dose escalation cohorts to determine the MTD of RP6530 using a standard 3+3 design, followed by two expansion cohorts enrolling 20 pts with peripheral T-cell lymphoma (PTCL) and 20 pts with cutaneous T-cell lymphoma (CTCL). Pts with a diagnosis of PTCL or CTCL who have received at least one prior systemic therapy, ECOG performance status ≤ 2 and measurable/evaluable disease are eligible. This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of RP6530 administered twice daily (BID) in 28-day cycles. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2014) and the modified Severity Weighted Assessment Tool (mSWAT) respectively. Dose limiting toxicity (DLT) was defined by a toxicity of grade 3/4 that is considered related to treatment during the first cycle of treatment. Results: To date eleven pts (6 PTCL and 5 CTCL) (5 males and six females) have been enrolled at three dose levels: 200 mg BID, 400 mg BID and 800 mg BID. ECOG performance status score was 0/1/2 in 10/1/0 pts, respectively, with a mean age of 68 yrs (range 52-76). Pts had a median of 3 (range: 3-6) prior treatment regimens, and 5 pts had refractory disease and 6 relapsed on prior treatments. RP6530 was well tolerated without any DLT or related serious adverse event reported to date. A total of 52 non-serious adverse events were reported: 41 Grade 1/2 and 11 Grade 3/4. The most common adverse events included mild vomiting (18%), diarrhoea (18%), fatigue (18%), and rash (18%). No Grade 3/4 adverse events were deemed related to RP6530 except for ALT/AST elevation in one pt. No pt discontinued treatment due to a safety issue. Dose-proportional increases in plasma concentrations were observed in PKs. Dose escalation is currently ongoing at 800 mg BID. Five pts were evaluated for responses at Cycle 3, Day1. Two pts (1 PTCL and 1 CTCL) experienced PR (40%) that are ongoing >5 months, and three pts experienced stable disease lasting for >3 months (60%). Three pts experienced rapid disease progression during first cycle, and discontinued treatment prematurely. Conclusion: This ongoing study of RP6530 demonstrated an acceptable safety profile at doses evaluated, with a promising clinical activity. The results support further evaluation of RP6530 in pts with mature T-cell neoplasms. Disclosures Oki: Novartis: Research Funding. Barde:Rhizen Pharmaceuticals SA: Employment. Penmetsa:Rhizen Pharmaceuticals SA: Employment. Viswanadha:Incozen Therapeutics: Employment.

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