Banoxantrone (AQ4N), a Tissue Targeted Prodrug: Results of a Phase 1 Study in Lymphomas.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2429-2429
Author(s):  
Richard R. Furman ◽  
Nancy L. Bartlett ◽  
Alvin F. Wong ◽  
Leanne M. McCulloch ◽  
Gilbert N. Lam ◽  
...  
Keyword(s):  
Partial Response ◽  
Follicular Lymphoma ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Topoisomerase Ii ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Blood Levels ◽  
Dna Intercalator ◽  
Grade 3

Abstract AQ4N is a prodrug which is selectively bioreduced by cytochrome P450 to AQ4, a potent DNA intercalator and topoisomerase II inhibitor. Preclinical studies demonstrate AQ4N selectively targets lymphoblastoid cell lines and hypoxic tumors. This study assessed the maximum tolerated dose (MTD), and pharmacokinetics (PK) of repeated dosing of AQ4N in patients (pts) with lymphoid malignancies. AQ4N was administered IV on Day 1 of a 21 day cycle to cohorts of at least three pts at doses of 400, 800, or 1200 mg/m2 for a maximum of 8 cycles. The dose was escalated as long as <33% of pts did not experience a dose limiting toxicity (DLT). 11 pts were enrolled with 3 pts treated at 400 mg/m2 and 4 pts treated at 800 and 1200 mg/m2 each. No pts experienced a DLT and no clinical MTD was identified. No further dose escalation was investigated due to reaching known maximum AQ4N solution solubility. The most common related adverse events (AE) observed were expected transient skin discoloration (100%), transient chromaturia (36%) and lymphopenia (27%), as well as fatigue (27%) and nausea (27%). AEs were primarily mild (Grade 1–2) with the exception of Grade 3 lymphopenias (n=3) and Grade 3 neutopenia (n=1) events. No dose reductions or dose delays resulted from these hematologic decreases. 6 pts experienced at least one serious AE, including: pneumonia, staph aureus bacteremia, acute respiratory distress syndrome (ARDS), dyspnea, and pleural effusion, none of which were attributed to AQ4N. The PK was linear over all doses studied. At 1200 mg/m2 (n=4), the Day 1 AQ4N Cmax was 122.3 ± 13.1 μg/mL, AUC0–∞ was 340.8 ± 68.7 μg·h/mL, and T1/2 was 3.2 h (range 2.8 to 4.1 h). One pt with follicular lymphoma dosed at 1200 mg/m2 had a partial response after the 4th cycle using the NHL standardized response criteria. The pt went on to complete all 8 cycles and to date remains in partial response. The bioreductive prodrug, AQ4N, is well-tolerated when administered on a repeated 21-day schedule at doses up to and including 1200 mg/m2. Further dose escalation was precluded since the known maximum solubility of AQ4N was reached. Blood levels of AQ4N achieved in this study appear to be within the range of potentially therapeutic levels of the active drug, AQ4, as seen in previous preclinical and clinical studies of solid tumors (Harris PA et al, 2006; Albertella MR et al., 2006). Preliminary evidence of anti-tumor activity was seen in one pt with follicular lymphoma. Further clinical studies of AQ4N administered both as a monotherapy and in combination with chemo- and radiation therapy are planned in B-cell neoplasms and solid tumor malignancies.

A phase I/II study of carfilzomib (CFZ) as a replacement for bortezomib (BTZ) for multiple myeloma (MM) patients (Pts) progressing while receiving a BTZ-containing combination regimen.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8098-8098 ◽  
Author(s):  
James R. Berenson ◽  
Ori Yellin ◽  
Robert Dichmann ◽  
Dipti Patel-Donnelly ◽  
Ralph V. Boccia ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase 1 ◽  
Single Agent ◽  
Pegylated Liposomal Doxorubicin ◽  
Maximum Tolerated Dose ◽  
Combination Regimen ◽  
Minor Response ◽  
Early Results ◽  
Grade 3 ◽  
Combination Regimens

8098 Background: Recent data has shown that single-agent CFZ can produce responses among MM pts refractory to previous treatment regimens including those containing BTZ. We conducted an intrapatient Phase 1/2 trial investigating the safety and efficacy of CFZ as a replacement for BTZ in BTZ‑containing regimens to which pts have progressed. Methods: Eligible pts had to have progressed while receiving their most recent BTZ‑containing regimen after at least 4 doses of BTZ at > 1.0 mg/m² in < 4 weeks per cycle. Combination regimens containing an alkylating agent, anthracycline, or a glucocorticosteroid were eligible. CFZ replaced BTZ in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each cycle. Treatment continued using the same dose(s) and schedule(s) of each drug administered in the BTZ‑containing regimen. CFZ doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m² or until a maximum tolerated dose (MTD) was reached for that regimen. Results: Of 19 enrolled pts 13 are evaluable to date and 6 have recently started treatment. Pts received a median of 7 (range, 1-18) prior treatments and 5 (range, 1-5) different BTZ-containing regimens. Pts were treated with CFZ and the following different combinations: bendamustine (BEND) alone, BEND + methylprednisolone, dexamethasone (DEX) alone, DEX + pegylated liposomal doxorubicin, ascorbic acid + cyclophosphamide, and melphalan alone. Pts have completed a median of 3 cycles. Clinical benefit was seen in 10 (77%) pts (complete response = 8%; very good partial response = 8%; partial response = 31%; minor response = 31%) with another 23% showing stable disease. The median time to progression (range: 2-8 months) has not been reached and only 2 pts have progressed. The most common grade 3/4 adverse events were thrombocytopenia occurring in 5 pts (all = grade 3 except 1 event) and fever occurring in two pts (grade 3). Four pts experienced a serious adverse event but no regimen has reached a MTD. Conclusions: These early results suggest that CFZ is an effective and tolerable replacement for BTZ for pts who are refractory to BTZ-containing combination regimens.

A phase I study of birinapant (TL32711) combined with multiple chemotherapies evaluating tolerability and clinical activity for solid tumor patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2504-2504 ◽  
Author(s):  
Ravi K. Amaravadi ◽  
Neil N. Senzer ◽  
Lainie P. Martin ◽  
Russell J. Schilder ◽  
Patricia LoRusso ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Clinical Benefit ◽  
Clinical Studies ◽  
Drug Exposure ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Drug Shortage ◽  
Apoptotic Pathway ◽  
Best Response

2504 Background: Birinapant (B) is a SMAC-mimetic that inhibits IAPs with excellent tolerability, drug exposure, target suppression and apoptotic pathway activation in clinical studies. Preclinical studies demonstrate potent anti-tumor synergy when B is combined with TNFa-inducing chemotherapies (CT). Methods: Escalating doses of B were combined with CT in a 5-arm 3+3 phase 1 study for adults (pts) with relapsed/refractory solid tumors to determine maximum tolerated dose (MTD), pharmacokinetics (PK), and efficacy to identify indications for further studies. The arms included carboplatin/paclitaxel (CP), irinotecan (I), docetaxel (D), gemcitabine (G), and liposomal doxorubicin (LD). Results: 124 pts were treated with B at doses of 2.8 to 47 mg/m2. The MTD of B for each arm was CP (47 mg/m2); I (22 mg/m2); D (47 mg/m2). The proposed G regimen could not be administered in heavily pretreated pts and B could not be evaluated for dose escalation; this arm was discontinued and no dose-limiting toxicities (DLT) occurred. LD drug shortage prevented dose escalation for B > 35mg/m2 (MTD not reached). B did not limit CT administration for CP, I, D, LD, supporting tolerable combination of B with CT. B-associated toxicity of Bell’s palsy (Grade 2) was considered a DLT and noted at higher dose levels for I, D, and LD, but not CP. This unusual reversible toxicity occurred during cycle 1 in 7 pts. Six of these pts continued therapy without recurrence. PK studies demonstrated no effect of B on CT. Except for CP, CT did not change the PK of B. CP increased plasma PK for B, possibly due to OATP1B3 transporter effects, but without increased B toxicities. 11 pts had a partial response, 61 pts had stable disease (>2 cycles, median 4.6 mo) and 37 pts had progressive disease as their best response, with clinical benefit (CR+PR+SD) of 58%. Conclusions: B can be combined with excellent tolerability with multiple CT at standard dosing. B plus CT demonstrated clinical benefit in many tumor types. Notable clinical activity occurred with I + B in pts who had failed prior I. These results support planning for further clinical studies of the I + B, and support the hypothesis for TNFa-mediated I + B synergy. Clinical trial information: NCT01188499.

A dose escalation phase 1 study of radiotherapy (RT) in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab in patients (pts) with metastatic melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9549-9549 ◽  
Author(s):  
Celine Boutros ◽  
Christine Mateus ◽  
Emilie Lanoy ◽  
Emilie Routier ◽  
Salem Chouaib ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Metastatic Melanoma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Tumor Control ◽  
Severe Toxicity ◽  
Phase 1 Study ◽  
Grade 3

9549 Background: Preclinical findings have shown a synergy between RT and anti-CTLA-4 monoclonal antibody in several tumor animal models for both local tumor control and distant effects. Preliminary clinical data suggest that it could be due to an abscopal effect of RT. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of RT combined with ipilimumab in pts with metastatic melanoma. Methods: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of RT (in 3 fractions) at week 4 combined with 10 mg/kg ipilimumab (every 3 weeks for 4 doses). Pts with evidence of clinical benefit at week 12 were eligible for maintenance ipilimumab at 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression based on immune-related response criteria (irRC). Results: 19 pts with advanced melanoma received ipilimumab between August 2011 and July 2015. Nine pts received the 4 doses of ipilimumab and 2 pts received maintenance ipilimumab (1 and 2 cycles respectively). All pts received the combined RT at week 4 in 3 fractions. All pts presented at least one AE of any grade. The most common AEs were asthenia, diarrhea, desease-related pain and fever. Grade 3 AEs occurred in 8 pts. They included colitis (n = 3), hepatitis (n = 2), anemia (n = 2), asthenia (n = 1), thyroid disorders (n = 1) and nausea/vomiting (n = 1). Nine pts discontinued the study owing to treatment-related adverse events including colitis (n = 6), hepatitis (n = 2) and DRESS (Drug Rash with Eosinophilia and systemic syndrome) (n = 1). DLT occurred in 2/6 pts in the cohort receiving 15 Gy. No drug-related death occurred. According to irRC, 4 partial responses (ORR: 21%) and 4 stable diseases were observed at week 24. The MTD was 9 Gy dose. One pt out of 12 treated in the 9 Gy cohort presented a DLT (grade 3 colitis). The median progression-free survival [95% CI] was 7.2 months [2.4 – 16.8]. The median overall survival [95% CI] was 14.4 months [7.2 – 20.4]. Conclusions: When combined with ipilimumab at 10 mg/kg, in the present design, the MTD of RT was 9 Gy. This combination appears to be associated with antitumor activity. Clinical trial information: 2010-020317-93.

Dose escalation and expansion from the phase I study of DS-1062, a trophoblast cell-surface antigen 2 (TROP2) antibody drug conjugate (ADC), in patients (pts) with advanced non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9619-9619 ◽  
Author(s):  
Aaron Elliott Lisberg ◽  
Jacob Sands ◽  
Toshio Shimizu ◽  
Jonathan Greenberg ◽  
Penny Phillips ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Escalation ◽  
Standard Treatment ◽  
Phase 1 ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Dose Effect ◽  
Antibody Drug Conjugate ◽  
Grade 3 ◽  
Experienced Grade

9619 Background: TROP2 is an intracellular calcium signaling transducer overexpressed in NSCLC, portending poor survival. DS-1062 is a TROP2-targeting ADC with a novel topoisomerase 1 inhibitor (exatecan derivative, DXd) and promising preclinical antitumor activity. Updated results inclusive of 24 additional dose escalation pts and 32 dose expansion pts from an ongoing phase 1 study of DS-1062 in advanced/metastatic NSCLC are reported (NCT03401385/J101). Methods: Pts aged ≥18 (US) or ≥20 (Japan) with unresectable NSCLC refractory to/relapsed from standard treatment with measurable disease (RECIST v1.1) and available tumor for retrospective TROP2 evaluation were eligible. Primary objectives include maximum tolerated dose (MTD) identification, safety, and tolerability and secondary objectives include efficacy, pharmacokinetics, and incidence of anti-drug antibodies against DS-1062. Pts were eligible regardless of TROP2 level. Results: As of November 16, 2019, 95 pts were treated with ≥1 dose of DS-1062. 63 pts were treated during escalation at 0.27 (n = 4), 0.5 (n = 5), 1.0 (n = 7), 2.0 (n = 6), 4.0 (n = 6), 6.0 (n = 19), 8.0 (n = 8), and 10.0 (n = 8) mg/kg and 32 pts were treated in expansion at the MTD of DS-1062, 8 mg/kg. 59 pts (62%) discontinued (25 [42%] due to progressive disease per RECIST v1.1). Pts were exposed to a median of 3 treatment cycles (range, 1-19). In 88 response-evaluable pts, 22 had partial response (1 PR/6 pts at 2.0 mg/kg, 2 PR/6 pts at 4.0 mg/kg, 5 PR/18 pts at 6.0 mg/kg, 13 PR/34 pts at 8.0 mg/kg, and 1 PR/8 pts at 10.0 mg/kg; 14 PRs were confirmed and 8 PRs are awaiting confirmation). Treatment emergent adverse events (TEAEs) regardless of causality were reported in 91 of 95 pts (96%; 44 pts [46%] experienced ≥grade 3, 30 pts [32%] had serious events). Treatment-related TEAES were reported in 76 of 95 pts (80%; 17 pts [18%] experienced ≥grade 3, 8 pts [8%]) had serious events). Potential interstitial lung disease (ILD) occurred in 8 pts (8%; 2 at 6.0 mg/kg and 6 at 8.0 mg/kg); 6/8 with potential ILDs adjudicated as treatment-related (1 at 6.0 mg/kg [grade 2] and 5 at 8.0 mg/kg [1 grade 1, 2 grade 2, 1 grade 3, and 1 grade 5]). 14 escalation pts and 22 expansion pts remain on trial. Updated trial details/results will be presented. Conclusions: In this first-in-human study of DS-1062, treatment was well tolerated up to 8 mg/kg, and a dose effect on antitumor activity was observed over 2.0-10.0 mg/kg in heavily pretreated pts with prior progression on standard treatment. Clinical trial information: NCT03401385 .

scholarly journals Weekly Carfilzomib, Cyclophosphamide and Dexamethasone (wCCd) in Newly Diagnosed Multiple Myeloma Patients: A Phase I- II Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 175-175 ◽  
Author(s):  
Antonio Palumbo ◽  
Davide Rossi ◽  
Sara Bringhen ◽  
Alessandra Larocca ◽  
Fabiana Gentilini ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Maximum Tolerated Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3

Abstract Background Carfilzomib is a novel second generation proteasome-inhibitor with significant anti MM activity and favorable toxicity profile, including very limited neurotoxicity and neutropenia. This Phase I/II study was designed to determine the maximum tolerated dose (MTD) of once weekly carfilzomib combined with cyclophosphamide-dexamethasone (wCCd) and to assess safety and efficacy of this combination in elderly patients with newly diagnosed MM. Here we report the first findings from the Phase I dose-escalation and expansion portions. Enrolment in the phase II portion is ongoing. Methods In the Phase I, the standard 3+3 dose-escalation scheme was adopted, with Carfilzomib as the only escalating agent starting at 45 mg/m2 (level 0), maximal planned dose 70 mg/m2 (level 2), and 36 mg/m2, if needed (level -1), given IV on days 1, 8, 15 in 28-day cycles. Oral cyclophosphamide was administered at 300 mg/m2 on days 1, 8, 15 and oral dexamethasone at 40 mg on days 1, 8, 15, 22 for all dose levels. Dose escalation of Carfilzomib was based on dose-limiting toxicities (DLTs) occurring in cycle 1. After completion of 9 cycles, patients receive 28-day maintenance cycles with Carfilzomib (days 1, 8, 15) at the maximum tolerated dose (MTD) defined by the Phase I study until disease progression or intolerance. The objectives were to determine the MTD and assess activity and safety. Results As of June 15, 2014, 28 newly diagnosed MM patients were enrolled. Median age was 74 years, 29% of patients were older than 75 years, 36% had ISS stage III, 24% had unfavorable FISH profile [t(4;14) or t (14;16) or del17p]. Twelve patients were enrolled in the Phase I portion of the study. At dose level 0 (Carfilzomib 45 mg/m2) no DLT was reported; at dose level 1 (Carfilzomib 56 mg/m2), 1 of 6 patients experienced DLT, consisting of grade 3 creatinine increase; at dose level 2 (Carfilzomib 70 mg/m2) no DLT occurred. The MTD of weekly Carfilzomib was thus established as 70 mg/m2. Toxicity and response data are available for 25 patients, who have completed at least the first cycle; 3 patients are currently receiving their first cycle of treatment. Grade 3-4 drug-related adverse events occurred in less than 15% of patients and included neutropenia (12%, 3 patients), anemia (12%, 3 patients), acute pulmonary edema (8%, 2 patients), pulmonary embolism (4%, 1 patient), creatinine increase (4%, 1 patient), nausea (4%, 1 patient), and fatigue (4%, 1 patient). No peripheral neuropathy was observed. Overall, the wCCd regimen was well tolerated, 3 patients (12%) required Carfilzomib dose reduction (grade 3 creatinine increase, grade 3 transaminase increase and grade 2 fever) and 3 patients (12%) required drug discontinuation due to adverse events (2 acute pulmonary edemas and 1 creatinine increase). Patients received a median of 5 cycles (range 1-9). After 4 induction cycles, 83% of patients achieved at least partial response, 39% at least very good partial response, and 22% complete response. Responses improved over time, as shown in table 1. During the study, only 2 patients progressed and 1 patient died, due to acute pulmonary edema considered probably related to treatment. Conclusions This is the first prospective study evaluating once weekly carfilzomib in treatment-naïve MM. wCCd therapy appears safe and effective in newly diagnosed MM patients. Responses became deeper with subsequent cycles and toxicities were manageable. The response rate observed with weekly carfilzomib compares favorably with similar studies with standard twice weekly carfilzomib infusion. Updated results will be presented at the meeting. Table 1 2nd cycle 4th cycle 6th cycle Complete Response 5% 22% 27% At least Very Good Partial Response 9% 39% 63% At least Partial Response 73% 83% 91% Disclosures Palumbo: Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Off Label Use: Use off-label of Carfilzomib (proteasome inhibitor).. Bringhen:Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria; Onyx: Consultancy. Larocca:Janssen Cilag: Honoraria; Celgene: Honoraria. Cavallo:Onyx: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gaidano:Onyx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Millenium: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Phase I study of BPM 31510 in advanced solid tumors: Updated analysis of a novel treatment with promising activity.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3015-3015
Author(s):  
Andrew Eugene Hendifar ◽  
Sant P. Chawla ◽  
Doris Quon ◽  
Victoria S Chua ◽  
Lita Fernandez ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Minor Response ◽  
Grade 3

3015 Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to reverse the aerobic glycolytic phenotype of cancer cells. Effector downstream signaling results in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor vasculature by modulation of VEGF. (NR Narain et al., Proceedings of AACR Meeting Abstracts 2011). Methods: A standard 3+3 phase I, dose-escalation study design was used in patients with advanced solid tumors refractory to standard treatment. Primary objectives were establishment of the maximum tolerated dose (MTD) and safety/pharmacokinetic (PK) correlates. Secondary objectives included exploratory pharmacodynamics (PD) and preliminary efficacy (RECIST-1.1) of BPM 31510 in sequential cohorts of 3 to 6 pts. Results: At time of submission, 34 patients with advanced cancer who had failed multiple chemotherapeutic regimens had been enrolled in 7 dose cohorts (ranging from 5.6 mg/kg to 78.2 mg/kg). Patients received a median of 2 cycles (1-7). 2 patients have had grade 3 elevation in PT/INR, otherwise there have been no grade 3/4 treatment related toxicities to date. The pharmacokinetics of BPM 31510 are linear and there were no sex differences in the parameters normalized by dose and body surface area. Tmax and Cmax are associated with the end of the infusion. The values for t1/2 ranged from 2.18 to 13.3 hr, with little or no dependence of t1/2 on dose. Objective tumor responses have been noted at the dose of 58.6mg/kg with 1 partial response (myxoid liposarcoma) and 1 minor response (pleomorphic sarcoma). Six patients (19%) have had disease stabilization (> 4 months). Conclusions: Interim data from this phase I study indicate that BPM 31510 is well tolerated with no dose limiting toxicities to date. A partial response and minor response were observed and correlates with dose escalation. Taken together, there is strong rationale for further clinical development of this compound as an anti-cancer agent.

Phase 1 study of infusional or bolus deflexifol (a novel formulation of 5FU, folinic acid, and cyclodextrin) after failure of standard treatment.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. TPS812-TPS812
Author(s):  
Philip R. Clingan ◽  
Stephen P. Ackland ◽  
Marie Ranson ◽  
Paul De Souza ◽  
Ali Tafreshi ◽  
...  
Keyword(s):  
Anticancer Drugs ◽  
Dose Escalation ◽  
Standard Treatment ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Advanced Malignancy ◽  
High Ph ◽  
Grade 3

TPS812 Background: 5FU is a commonly used anti-cancer agent first synthesized in 1957, and is now most commonly used in combination with FA, which enhances its clinical activity. Physical incompatibilities between 5FU and LV necessitate the infusion of each component separately, often through a central line due to high pH; resulting in adverse events, which leads to poor outcomes due to treatment interruption and discontinuation. A novel all in one reformulation of 5FU/LV at physiological pH has been developed as an alternative to serial administration of 5FU and LV in a high Ph solution [Locke JM, Anticancer Drugs 2009]. Preclinical testing demonstrated that the reformulation is stable bioequivalent to 5FU with reduced side effects [Stutchbury TK, Anticancer drugs 2011]. Methods: An open label phase 1 dose escalation study is underway in 2 schedules (bolus and infusion) to assess the safety and tolerability in patients with advanced malignancy after failure of standard treatment (including fluoropyrimidine regimens). To determine the maximum tolerated dose defined as: 2 out of 6 patients experience DLTs dose escalation is halted and declared DLT Dose. The previous dose level will be considered for expansion to x6 patients to confirm Maximum Tolerated Dose (MTD). Also to determine pharmacokinetic profile. Patients enrolled in Cohorts 1 to 4, have been completed without DLT. Dose-limiting toxicity (DLT) is defined as: Any Grade 3 or 4 non-haematologic toxicity (CTACE criteria). Patients developing Grade 3 or 4 diarrhoea, failing maximal anti-diarrheal medications. Febrile neutropenia, Grade 4 neutropenia > 7 days, Grade 4 thrombocytopenia > 7 days Any grade of thrombocytopenia associated with bleeding. Currently proceeding with (bolus 575mg/m2 weekly x 6, infusion 3600mg/m2/46h q2W). Limited sampling PK of 5-FU and dihydoFU is being conducted (3 at each of the 5 dose levels, doses 1 and 6). In both schedules to assess PK variability, adequacy of dosing in comparison to previous reports. The incidence of AEs and SAEs (CTACE 4.03) will be summarized by severity and relationship to study treatment. Clinical trial information: 044867.

Phase 1 dose escalation study of XMT-1536, a novel NaPi2b-targeting antibody-drug conjugate (ADC), in patients (pts) with solid tumors likely to express NaPi2b.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3010-3010
Author(s):  
Anthony W. Tolcher ◽  
Susanna Varkey Ulahannan ◽  
Kyriakos P. Papadopoulos ◽  
William Jeffery Edenfield ◽  
Ursula A. Matulonis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Systemic Exposure ◽  
Maximum Tolerated Dose ◽  
Antibody Drug Conjugate ◽  
Dose Escalation Study ◽  
Grade 3

3010 Background: XMT-1536 is a Dolaflexin ADC targeting the sodium-phosphate cotransporter NaPi2b, expressed in ovarian, non-squamous lung, papillary thyroid, endometrial, papillary renal and salivary duct cancers. Methods: In this ongoing Phase 1 study, pts with solid tumors likely to express NaPi2b, who progressed on standard therapy, are treated with intravenous XMT-1536 using a 3+3 design with a modified Fibonacci escalation. NaPi2b expression by IHC is being examined retrospectively in archived tumors. Primary objectives in dose escalation are safety and tolerability and determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). (ClinicalTrials.gov NCT03319628). Results: As of Jan. 28, 2019, 36 pts (22 ovarian, 7 endometrial, 4 NSCLC, 3 other) have received treatment with XMT-1536. Treatment was initially given every 3 weeks (q3w); 20 pts were treated in dose cohorts from 3 to 40 mg/m2. There was one DLT of reversible AST elevation at 40 mg/m2. The dosing interval was then changed to every 4 weeks (q4w), and dose escalation was restarted at 20 mg/m2. There was one DLT of reversible AST elevation at 30 mg/m2 on the q4w schedule. Further followup and dose escalation are ongoing. The most common (≥10% of patients) treatment-related adverse events (TRAEs) have been nausea, fatigue, headache, increased AST, anorexia, increased alkaline phosphatase, fever, increased GGT, myalgia, and vomiting. Grade 3 TRAEs were reversible AST increases in 3 patients and increased GGT, decreased lymphocytes, and systolic congestive heart failure in 1 patient each. Treatment-related serious AEs of fever and systolic congestive heart failure occurred in 1 patient each. Among patients dosed at 20 mg/m2 or higher who had restaging scans (n=20), there were 2 PR, in ovarian cancer pts at 30 mg/m2 q3w and 20 mg/m2 q4w, and 11 SD, with disease control maintained for up to 24 weeks. Patient-level results for NaPi2b expression will be presented. The systemic exposure of total payload showed approximately dose-proportional increase. Plasma concentration of free drug payload and its active metabolite were low. Conclusions: XMT-1536 has been well-tolerated up to the 30 mg/m2 dose level with early signs of anti-tumor activity. Dose escalation continues in pts with advanced solid tumors likely to express NaPi2b. Clinical trial information: NCT03319628.

scholarly journals A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis

Blood ◽  
2017 ◽  
Vol 130 (5) ◽  
pp. 597-605 ◽  
Author(s):  
Vaishali Sanchorawala ◽  
Giovanni Palladini ◽  
Vishal Kukreti ◽  
Jeffrey A. Zonder ◽  
Adam D. Cohen ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Subcutaneous Tissue ◽  
Phase 1 ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Al Amyloidosis ◽  
Grade 3

Abstract This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902. A phase 3 study is ongoing (#NCT01659658).

scholarly journals Phase 1 trial of apatinib combined with intensity-modulated radiotherapy in unresectable hepatocellular carcinoma

2021 ◽  
Author(s):  
Hongzhi Wang ◽  
Xianggao Zhu ◽  
Yuting Zhao ◽  
Dezuo Dong ◽  
Lijuan Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Objective Response ◽  
Local Treatment ◽  
Intensity Modulated Radiotherapy ◽  
Maximum Tolerated Dose ◽  
Intensity Modulated ◽  
Unresectable Hepatocellular Carcinoma ◽  
Grade 3

Abstract Background To investigate the maximum tolerated dose (MTD) of apatinib delivered during and after intensity-modulated radiotherapy (IMRT) for unresectable hepatocellular carcinoma (HCC). Methods Patients with unresectable HCC who were not eligible for radiofrequency ablation (RFA), transarterial chemoembolization (TACE), or residual/recurrent after the prior local treatment were enrolled. Patients were scheduled to be treated with IMRT at 50–60 Gy/25–30 fractions. Apatinib was administered concurrently with IMRT and continued after IMRT. In this study, we used a 3 + 3 dose-escalation design. Three dose levels of apatinib (250, 500, and 750mg) were designed. Grade 3 or more severe adverse events (AEs) were defined as dose-limiting toxicities (DLTs). The treatment response was calculated using the Modified Response Evaluation Criteria in Solid Tumour. Results Nine patients with Barcelona Clinic Liver Cancer stage C were included in this study. One patient withdrew from the apatinib 250mg group and another patient was added. No DLT occurred in the apatinib 250mg group. Five patients were included in the apatinib 500mg group, and 2 cases of DLT (grade 3 leukopenia) were found among them. Dose escalation was terminated and the MTD was determined to be 250mg. Common AEs of grade 1–2 included fatigue, hypertension, dizziness, bone marrow suppression, and hyperbilirubinemia. The median follow-up time for all patients was 16.0 months. Three patients achieved complete response and another three achieved partial response. The objective response rate was 6/9 (66.7%), and the disease control rate was 9/9 (100%). Three patients relapsed out of the radiation field. The median progression-free survival was 17.0 months, and the median overall survival was 16.7 months. Conclusions When combined with IMRT, apatinib 250mg daily was recommended for a phase 2 study of unresectable HCC. The antitumor activity of the combination treatment was encouraging. The safety and efficacy of apatinib combined with IMRT for unresectable HCC should be further investigated in future studies.

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