2-Chlorodeoxyadenosine dose escalation in nonhematologic malignancies.

1993 ◽  
Vol 11 (4) ◽  
pp. 671-678 ◽  
Author(s):  
A Saven ◽  
H Kawasaki ◽  
C J Carrera ◽  
T Waltz ◽  
B Copeland ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Intravenous Infusion ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
Malignant Astrocytoma ◽  
Dose Escalation Study ◽  
Tissue Samples ◽  
Grade 3 ◽  
Higher Doses ◽  
Experienced Grade

PURPOSE We performed a dose-escalation study of 2-chlorodeoxyadenosine (2-CdA) in solid tumors to determine the maximum-tolerated dose (MTD) and define its toxicity profile at higher doses. PATIENTS AND METHODS Twenty-one patients, seven with malignant astrocytoma, twelve with metastatic melanoma, and two with metastatic hypernephroma, were enrolled onto the study. Patients were entered onto cohorts that received 0.10, 0.15, or 0.20 mg/kg/d of 2-CdA by continuous intravenous infusion for 7 days every 28 days. 2-CdA levels were determined by radioimmunoassay. In tumor tissue samples, deoxycytidine kinase (dCK) levels were measured by both enzyme activity and immunoreactive protein analysis. RESULTS Of seven patients treated with 2-CdA at 0.1 mg/kg/d, one experienced grade 3 or 4 myelotoxicity. Of 11 patients treated at 0.15 mg/kg/d, four experienced myelotoxicity, two after a single course of 2-CdA. All three patients who received 2-CdA at 0.2 mg/kg/d experienced myelosuppression. Neurologic events occurred in two patients, both with malignant melanoma. Two of seven patients (28.6%) with astrocytomas obtained partial responses with a median duration of 8 months. 2-CdA penetrated the blood-brain barrier. An association was found between dCK levels as measured by enzymatic activity and immunoreactive proteins, but this did not correlate with 2-CdA tumor responsiveness. CONCLUSION The MTD for 2-CdA delivered as a 7-day intravenous infusion in patients with nonhematologic malignancies was determined to be 0.1 mg/kg/d, the same as the MTD for patients with hematologic malignancies. There was no clinical correlation with dCK expression and response to 2-CdA. The responses noted in patients with malignant astrocytoma warrant further phase II study.

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

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6055-6055 ◽  
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]

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.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3025-3025 ◽  
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.

A phase lb, open-label, multicenter, dose-escalation study of the oral pan-PI3K inhibitor BKM120 in combination with the oral MEK1/2 inhibitor GSK1120212 in patients (pts) with selected advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3003-3003 ◽  
Author(s):  
Philippe Bedard ◽  
Josep Tabernero ◽  
Razelle Kurzrock ◽  
Carolyn D. Britten ◽  
Anastasios Stathis ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Plasma Concentrations ◽  
Oral Intake ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Bayesian Logistic Regression

3003 Background: MAPK and PI3K/AKT signaling pathways regulate proliferation, differentiation and cell death in human cancers. Known interaction between the 2 pathways provides the rationale for combining both inhibitors in a phase I study. Methods: The objective is to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) for oral, daily administered, BKM120 + GSK1120212, mainly in pts with tumors with RAS/RAF mutations (mt). A Bayesian logistic regression model with overdose control guides the dose escalation of the treatment. Secondary objectives include safety, tolerability, PK and efficacy. Results: As of 22.09.11, 49 pts were treated with BKM120 + GSK1120212 as follows: 30mg + 0.5mg, 60mg + 0.5mg, 60mg + 1.0mg, 60mg + 1.5mg, 60mg + 2.0mg, 70mg + 1.5mg, 80mg + 1.0mg, 80mg + 1.5mg. 6 pts had dose-limiting toxicities (DLTs); all were reversible. Grade 3 DLTs were: 3 x stomatitis, 1 x dysphagia, 1 x LVEF decrease, 1 x CK increase, 1 x nausea, 1 x anorexia, 1 x decreased oral intake. MTD and/or RP2D for the combination have not been reached. Most common adverse events (AEs) (>25%), all grades and causality, were dermatitis acneiform, diarrhea (51% each); nausea (41%); vomiting (37%); rash (33%); asthenia (31%); CK increase, decreased appetite, pyrexia or stomatitis (29% each) and hyperglycemia (27%). There were 4 on-treatment deaths unrelated to treatment. AEs led to treatment discontinuation, 17 pts (35%) and interruptions/dose reductions, 25 pts (51%). Apparent steady-states of BKM120 and GSK1120212 were reached by day 28. Plasma concentrations of BKM120 in combination with GSK1120212 were lower than for monotherapy. Exposure to GSK1120212 with BKM120 was similar to that observed in monotherapy studies. 3 confirmed partial responses have been observed in pts with KRAS mt ovarian cancer; 2 lasting >9 months. 2 patients with BRAF mt melanoma, who had previously progressed on BRAF inhibitors, had stable disease, for 1 of whom treatment is still ongoing in cycle 6. Conclusions: BKM120 and GSK1120212 can be safely combined. Signs of clinical activity have been seen in pts with RAS/RAF mt tumors.

A phase I, first-in-human, open-label, dose-escalation study of MGD013, a bispecific DART molecule binding PD-1 and LAG-3, in patients with unresectable or metastatic neoplasms.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3004-3004
Author(s):  
Jason J. Luke ◽  
Manish R. Patel ◽  
Erika Paige Hamilton ◽  
Bartosz Chmielowski ◽  
Susanna Varkey Ulahannan ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Flow ◽  
Open Label ◽  
Dose Escalation Study ◽  
Combination Methods ◽  
Label Dose ◽  
Specific Expansion ◽  
Target Binding

3004 Background: MGD013 is an investigational, first-in-class, Fc-bearing bispecific tetravalent DART molecule designed to bind PD-1 and LAG-3 and sustain/restore the function of exhausted T cells. MGD013 demonstrates ligand blocking properties consistent with anti-PD-1 and anti-LAG-3 benchmark molecules, and improves T cell responses beyond that observed with benchmark or component antibodies alone or in combination. Methods: This study characterizes the safety, tolerability, dose-limiting toxicities, maximum tolerated dose (MTD), PK/PD, and antitumor activity of MGD013 in patients (pts) with advanced solid and hematologic malignancies. Sequential single-pt cohorts were treated with escalating flat doses of MGD013 (1-1200 mg IV every 2 weeks), followed by a 3+3 design. Tumor-specific expansion cohorts are being treated at the recommended Phase 2 dose of 600 mg. Results: At data-cutoff, 50 pts (46% checkpoint-experienced) were treated in Dose Escalation, and 157 pts (32% checkpoint-experienced) in Cohort Expansion. No MTD was defined. Treatment-related adverse events (TRAEs) occurred in 146/207 (70.5%) pts, most commonly fatigue (19%) and nausea (11%). The rate of Grade ≥ 3 TRAEs was 23.2%. Immune-related AEs were consistent with events observed with anti-PD-1 antibodies. Mean half-life was 11 days; peripheral blood flow cytometry analyses confirmed full and sustained on-target binding during treatment at doses ≥ 120 mg. Among 41 response-evaluable [RE] dose escalation pts, 3 confirmed partial responses [cPRs] (triple negative breast cancer [TNBC], mesothelioma, gastric cancer) per RECIST 1.1 were observed, while 21 pts had stable disease [SD]. Among select expansion cohorts, PRs have been observed in epithelial ovarian cancer (n=2; both cPRs, and 7 with SD among 15 RE pts) and TNBC (n=2; 1 cPR, 1 unconfirmed PR [uPR], and 5 with SD among 14 RE pts). In a cohort of pts with HER2+ tumors treated with MGD013 in combination with margetuximab (investigational anti-HER-2 antibody), 3 PRs have been observed (breast [n=2], colorectal [n=1]; 1 cPR, 2 uPRs) and 2 pts with SD among 6 RE pts. Objective responses have been observed in several pts after prior anti-PD-1 therapy. Investigations into potential correlative biomarkers including LAG-3 and PD-1 are ongoing. Conclusions: MGD013, a novel molecule designed to coordinately block PD-1 and LAG-3, has demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity. Clinical trial information: NCT03219268 .

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 .

Phase I/II Study of Bortezomib in Combination with Liposomal Doxorubicin and Melphalan in Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5182-5182 ◽  
Author(s):  
Ajai Chari ◽  
Lawrence Kaplan ◽  
Charles Linker ◽  
Lloyd E. Damon ◽  
Willis H. Navarro ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Heavily Pretreated ◽  
Level 1 ◽  
Grade 3

Abstract Phase I/II studies using either liposomal doxorubicin (D) or oral melphalan (M) in combination with the proteasome inhibitor bortezomib (V) have found favorable efficacy and tolerance in patients with relapsed and refractory MM. Since these drugs have different mechanisms of action and toxicity profiles, we initiated a phase I/II study to examine the safety and efficacy of combining all three agents (DMV) in relapsed or refractory myeloma. Study Aims: Starting at 25–50% of the doses used in the two drug combination studies, the objective of this dose escalation study was to evaluate the safety/tolerability of DMV until the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) could be identified. Efficacy was also evaluated. Methods: Patients with relapsed/refractory MM and progressive disease requiring treatment were enrolled in the study. Dose level 1 consisted of D 10 mg/m2 and M 5 mg/m2 given IV on day 1 with V given by IV push on days 1, 4, 8, and 11. Cycles were repeated every 28 days up to a maximum of 6 cycles. Dose levels of D, M, V (mg/m2) in the subsequent three cohorts were (10, 10, 0.7), (20, 10, 0.7), and (20, 10, 1.0) respectively. Once the MTD has been identified, an additional 17 patients will be enrolled at this dose level in the phase II portion of the study. Results: 5 patients (2 males, median age 65, range 33–79) have been enrolled in the study thus far. The myeloma subtypes include 2 IgG, 1 IgA, and 2 with light chains only. In this heavily pretreated population (range 2–7 prior therapies), 4 patients received prior autologous stem cell transplantation, 2 had a prior nonmyeloablative allogenic transplant, 4 prior VAD, 1 prior bortezomib, 2 prior oral melphalan, 3 prior thalidomide, 2 prior CC-5013, and 2 prior spinal radiation. The first dose cohort has been completed without any DLT. One patient had 3 days of Grade 3 neutropenia. All other toxicities were Grade 1–2 including asthenia, vomiting, thrombocytopenia, and headache. Of note, a patient with baseline Grade 2 peripheral neuropathy and on hemodialysis remained stable. A patient with Grade 2 chronic graft versus host disease also remained stable. Four patients have been enrolled at dose level one. One patient, who had progressive disease after an autologous and a nonmyeloablative allogenic transplant as well as CC5013, had a near CR (IFE+) after the second cycle of DMV. Two patients have had stable disease. One had disease progression after one cycle and subsequently died. The patient on dose level two is too early to evaluate. Conclusion: Thus far, DMV appears to be well tolerated and no DLT has been observed even in elderly patients with significant comorbidities. The finding of a near CR and SD at only dose level 1 is encouraging particularly since the patients were significantly pretreated. Dose escalation continues to determine the MTD.

A Phase I Study of Cloretazine® and Temozolomide in Patients with Hematologic Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1971-1971 ◽  
Author(s):  
David A. Rizzieri ◽  
William Tse ◽  
Khuda D. Khan ◽  
Anjali Advani ◽  
Jon Donze ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Single Agent ◽  
Pulmonary Hemorrhage ◽  
Hematologic Malignancies ◽  
Hematologic Toxicity ◽  
Dose Escalation Study ◽  
Futile Cycle ◽  
Grade 3 ◽  
Dna Strand

Abstract Background: In recent single agent Phase I trials, both Cloretazine® (VNP40101M) and temozolomide (TMZ) have shown activity in relapsed leukemia with minimal non-hematologic toxicity (Giles et al, 2004, Seiter et al, 2002). The cytotoxic activity of Cloretazine and TMZ have been attributed to the alkylation at the O6 position of guanine leading to a futile cycle of misincorporation of thymidine and ineffective mismatch repair. In addition, activation of Cloretazine generates different alkylating and isocyanate species that produce DNA cross linkages leading to DNA strand breaks and apoptosis. Repair of Cloretazine and TMZ induced alkylation lesions have been attributed to the expression and irreversible activity of enzyme O6 alkylguanine DNA alkyltranferase (AGT). It has been shown that TMZ administered to patients once or twice daily can reduce AGT levels in tumor cells; therefore depletion of AGT by TMZ may sensitize cells to Cloretazine and result in synergistic anti-tumor activity. Methods: Cloretazine given after TMZ priming is currently evaluated in a Phase I dose escalation study. Patients are eligible if they have relapsed or refractory leukemia (ECOG 0–2). TMZ was given orally starting at a dose of 200 mg twice daily for 5 doses. Cloretazine is given intravenously on day 3, 2–4 hours after the last dose of TMZ starting at 100 mg/m2. Dose escalation of TMZ was guided by AGT depletion in leukemic blasts assessed by enzyme assay and HPLC (Gerson et al, 1985). Leukemia response is assessed according for standard criteria for CR and CRp (Cheson et al, 2003). Results: Thirty-two patients have been treated in the first 5 cohorts (I: 200mg TMZ +100mg/m2 Cloretazine n=7, II: 300mg TMZ+100mg/m2 Cloretazine n=6, III: 300mg TMZ + 200mg/m2 Cloretazine n=3, IV: 300 mg TMZ + 300mg/m2 Cloretazine n=7, V: 300 mg TMZ + 400mg/m2 Cloretazine n=9). Median age of the patients is 62 years (range 27–80), M:F = 20:12. Treatment with 300mg TMZ x 5 doses resulted in >90% depletion of AGT levels in 5 of 6 patients in cohort II and was fixed for subsequent dose escalation with Cloretazine. Myelosuppression was the most frequent adverse event occurring in 10/32 (30%) of treated patients (6 Grade 3–4 neutropenia, 4 Grade 3–4 thrombocytopenia). Non-hematologic toxicity has been minimal. To date, two patients treated with TMZ 300mg x 5 and Cloretazine 400 mg/m2 have experienced dose-limiting toxicity: Grade 3 pulmonary hemorrhage and Grade 3 neutropenic colitis in Cohort V and no unexpected toxicities were observed. Three early deaths occurred within 30 days (9.4%), all attributed to progressive disease. Responses are as follows: CR=3, CRp=1, and HI=2 for an overall response rate of 18.8%. The study is ongoing. Conclusions: Cloretazine® in combination with TMZ is tolerable and manageable. Evidence of anti-tumor effect has already been observed suggesting the combination of Cloretazine® and TMZ may potentiate their antileukemic activity.

Phase I study of rapamycin (R) in combination with CYP3A4 modifier, ketoconazole (K), in patients with advanced malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3061-3061
Author(s):  
E. E. Cohen ◽  
K. Moshier ◽  
F. Innocenti ◽  
M. Kocherginsky ◽  
L. House ◽  
...  
Keyword(s):  
Maximum Tolerated Dose ◽  
Advanced Malignancies ◽  
Starting Dose ◽  
Constant Dose ◽  
Cancer Types ◽  
Grade 3 ◽  
Elevated Transaminases ◽  
Dose Levels ◽  
Higher Doses ◽  
Experienced Grade

3061 Background: R is currently FDA approved for the treatment of renal allograft rejection but mTOR is a relevant target in several cancer types. K, a CYP3A4 inhibitor, increases the area under the concentration curve (AUC) of R and co-administration of R and K can overcome poor R bioavailability and decrease costs substantially. The aims of this study were to find the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of R administered weekly in combination with K and describe the pharmacokinetics (PK) of the combination in patients with advanced malignancies. Methods: R and K were administered concurrently to successive cohorts of patients. R starting dose was 1 mg once weekly and was escalated by 1 mg per dose level. K was administered at a constant dose of 200mg BID 1 day prior to each R dose then 200 mg QD on the next 3 consecutive days. Results: 34 subjects (median age 60 years) have been enrolled. The highest dose of R administered thus far was 5mg without DLT. Most frequent toxicities observed of any grade included hyperglycemia (41%), lymphopenia (35%), hyperlipidemia (35%), fatigue (29%), anemia (26%), anorexia (24%), and nausea (24%). Observed grade 3 toxicities included 2 patients with lymphopenia, 2 patients with elevated transaminases, and 1 patient each with emesis and hyperglycemia. One patient experienced grade 3 confusion likely due to a drug-drug interaction of K with concomitant psychotropic medications. PK analysis of the first 2 dose levels confirms that K significantly increases Cmax and AUC of R ( Table ). R Cmax (with K) averaged 22.5 (11.7) and 27.4 (7.9) (mean/SD) ng/ml at the 1 and 2 mg dose levels, respectively. R AUC (with K) averaged 408.9 (225.4) and 663.8 (201.8) (mean/SD) ng*h/ml at the 1 and 2 mg dose levels, respectively. Conclusions: Low dose weekly R plus K results in potentially efficacious concentrations, as demonstrated by classic mTOR inhibitor toxicity. Higher doses on this schedule without K are probably also feasible, but would have higher costs. [Table: see text] No significant financial relationships to disclose.

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.

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