Phase I study of oral gemcitabine prodrug (LY2334737) alone and in combination with erlotinib in patients (pts) with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2576-2576
Author(s):  
S. Koolen ◽  
P. O. Witteveen ◽  
I. Garcia-Ribas ◽  
S. Callies ◽  
V. Andre ◽  
...  
Keyword(s):  
Single Agent ◽  
Hypovolemic Shock ◽  
Hepatic Function ◽  
Maximum Tolerated Dose ◽  
Continual Reassessment ◽  
Proportional Increase ◽  
Grade 3 ◽  
Ecog Ps ◽  
Dose Levels ◽  
Further Development

2576 Background: LY2334737 (LY) is an orally available valproic acid prodrug of gemcitabine that was developed to overcome the extensive first-pass metabolism of gemcitabine to 2',2'-difluorodeoxyuridine (dFdU). The objectives of this study were to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetics (PK) of LY as monotherapy and in combination with erlotinib. Methods: Eligible pts had ECOG PS < 2 and adequate hematologic, renal and hepatic function. In Arm A, LY was given daily for 14 days in a 3-week cycle. Pts assigned to Arm B also received erlotinib daily 100 mg continuously. Dose escalation was based on observed toxicity and the modified continual reassessment method (mCRM). The dose was maximally increased by 100% depending on the toxicity observed in the previous cohort. PK of LY, gemcitabine, dFdU and intracellular metabolites were determined. Results: 33 pts (21 m, 12 f, median age 60 yrs (range 24–81)) were treated at 5 different dose-levels (range 5–50 mg/day). Pts received a median of 3 cycles (range 2–17). Three out of 7 pt treated with 50 mg experienced 5 dose limiting toxicities (DLT). DLTs observed at 40 and 50 mg include fatigue (4 pt), thrombocytopenia (1 pt), GGT elevation (1 pt), AST/ALT elevation (1 pt), fever (1 pt), and pulmonary embolism (1 pt). One death was possibly related to LY intake. This pt, treated with 40 mg LY, developed on day 15 dyspnea, hypovolemic shock, and suddenly died. No grade 3 or 4 toxicities were reported at dose-levels < 40 mg. The most common adverse events were fatigue, vomiting, nausea, pyrexia, anorexia, and diarrhea. Two pts with mesothelioma were stable for > 9 months. One pt with refractory prostate cancer presented a PSA CR as assessed by investigator. The PK show dose-proportional increase in exposure of both LY and gemcitabine. Both LY and gemcitabine are rapidly cleared, thus no accumulation occurs. The metabolite dFdU accumulates due to its long half life. Conclusions: LY displays linear PK. The dose level of 50-mg is non-tolerable and 40-mg is being confirmed as the MTD as single agent and in combination with 100 mg erlotinib. Antitumor activity warrants further development. Pt accrual is ongoing. [Table: see text]

Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of HDM-2 antagonist JNJ-26854165 in patients with advanced refractory solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3514-3514 ◽  
Author(s):  
J. Tabernero ◽  
L. Dirix ◽  
P. Schoffski ◽  
A. Cervantes ◽  
J. Capdevila ◽  
...  
Keyword(s):  
Liver Function Tests ◽  
Hepatic Function ◽  
Maximum Tolerated Dose ◽  
Preclinical Studies ◽  
Qtc Prolongation ◽  
Dose Escalation Study ◽  
Electrolyte Disturbances ◽  
Grade 3 ◽  
Ecog Ps ◽  
Dose Levels

3514 Background: JNJ-26854165 is a novel first-in-clinic oral Human Double Minute-2 (HDM-2) ubiquitin ligase antagonist. It increases the level of HDM-2 client proteins (e.g. p53) by inhibiting the association of HDM-2-client protein complex with the proteosome. Preclinical studies have demonstrated potent anti-proliferative and apoptosis-inducing activity of JNJ-26854165 in a broad range of p53 wild type and mutant tumor models. Methods: A 3+3 dose escalation study with the primary objectives to determine the adverse event (AE) profile, dose limiting toxicities (DLT) and maximum tolerated dose of JNJ-26854165 is ongoing. Secondary objectives include evaluation of PK and PD activity. Eligible patients have ECOG PS≤2 and adequate hematological, renal and hepatic function. JNJ-26854165 is administered orally once daily on a continuous schedule (21-day cycles). Sequential skin and tumor biopsies are taken, and evaluations for HDM-2, p53 and other pathway related markers are performed, including further molecular analyses for HDM-2 activity. Results: 37 pts have been treated at 9 dose levels (DL), 4–300 mg qd. AEs included nausea, vomiting, fatigue, anorexia, insomnia, electrolyte disturbances, liver function tests and creatinine elevations, and asymptomatic QTc prolongation, mostly grade 1–2. A DLT, grade 3 QTcF prolongation, was observed in one patient at DL 9. The patient was asymptomatic and the QTc prolongation recovered after treatment discontinuation. PK data showed dose-proportionality. After dosing at 300 mg, steady state Cmax and AUC0–24h were 2–3 μg/mL and ≈50 μg.h/mL, respectively, well exceeding the expected effective exposure modeled by preclinical studies. PD data showed engagement of the targeted pathway such as dose-dependent p53 upregulation in skin, upregulation of HDM-2 levels in tumors after treatment, and an increase in plasma MIC-1 levels. No objective responses have been observed so far. Conclusions: JNJ-26854165 was well tolerated at doses beyond the expected effective exposure modeled by preclinical studies. PD activity was observed at the 150–300 mg dose levels. The trial continues with cohort expansion at 300 mg. Updated results will be presented. [Table: see text]

Safety and pharmacokinetics of intravenous VEGF Trap plus FOLFOX4 in a combination phase I clinical trial of patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13061-13061 ◽  
Author(s):  
M. Mulay ◽  
S. A. Limentani ◽  
M. Carroll ◽  
E. S. Furfine ◽  
D. P. Cohen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Angiogenesis Inhibitor ◽  
Maximum Tolerated Dose ◽  
Vegf Receptor ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Ecog Ps ◽  
Dose Levels ◽  
Vegf Trap

13061 Background: VEGF Trap is a potent angiogenesis inhibitor comprising portions of human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (KDR) extracellular domains fused to the Fc portion of human IgG. VEGF Trap binds VEGF and neutralizes all VEGF-A isoforms plus placental growth factor. FOLFOX4 is an approved chemotherapy regimen for the treatment of colorectal cancer. This study was designed to evaluate the safety and pharmacokinetics (PK) of VEGF Trap plus FOLFOX4 administered intravenously. Methods: Successive cohorts of 3–6 patients (pts) with advanced solid tumors received intravenous VEGF Trap plus FOLFOX4 every 2 weeks. Study endpoints included safety, PK, and immunogenicity. Antitumor activity was assessed by CT scan. Results: Six pts (3 male/3 female), median age 55 (25–74), ECOG PS 0/1/2: 2/4/0, with a variety of advanced solid tumors, including 2 gastric and 2 neuroendocrine tumors, have received a total of 19 cycles of VEGF Trap plus FOLFOX4 across 2 VEGF Trap dose levels (2.0 mg/kg, 4.0 mg/kg) to date. Three of these 6 pts had grade 3 AEs (hypertension [n=2], neutropenia [n=2]), which were manageable and reversible. However, no dose-limiting toxicities or grade 4 AEs have been encountered so far. Preliminary mean free VEGF Trap clearance was 17.1 mL/kg/day. No pts have developed anti-VEGF Trap antibodies. Conclusions: VEGF Trap may be safely combined with FOLFOX4 at the dose levels studied. Preliminary free VEGF Trap clearance did not differ significantly from that seen with single-agent exposure; chemotherapy PK analysis is pending. The maximum tolerated dose has not yet been reached, and dose escalation continues. Updated safety, pharmacokinetic, and preliminary efficacy results from this ongoing study will be presented. [Table: see text]

Safety and pharmacokinetics of intravenous VEGF Trap plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in a combination phase I clinical trial of patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13161-13161 ◽  
Author(s):  
O. Rixe ◽  
C. Verslype ◽  
J. B. Méric ◽  
S. Tejpar ◽  
J. Bloch ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Angiogenesis Inhibitor ◽  
Maximum Tolerated Dose ◽  
Vegf Receptor ◽  
Advanced Solid Tumors ◽  
Colon Cancers ◽  
Ecog Ps ◽  
Dose Levels ◽  
Vegf Trap

13161 Background: VEGF Trap is a potent angiogenesis inhibitor comprising portions of human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (Flk-1) extracellular domains fused to the Fc portion of human IgG. VEGF Trap binds VEGF and neutralizes all VEGF-A isoforms plus placental growth factor. I-LV5FU2 is an approved chemotherapy regimen for the first-line treatment of metastatic colorectal cancer. This study was designed to evaluate the safety and pharmacokinetics (PK) of VEGF Trap plus I-LV5FU2 administered intravenously. Methods: Successive cohorts of 3–6 patients (pts) with relapsed or refractory solid tumors received intravenous VEGF Trap plus I-LV5FU2 every 2 weeks. Study endpoints included safety, PK, and immunogenicity. Antitumor activity was assessed by CT scan. Results: Ten pts (3 male/7 female), median age 59 (34–67), ECOG PS 0/1/2: 8/2/0, with a variety of advanced solid tumors, including 5 colorectal and 2 ovarian, have received a total of 50 cycles of VEGF Trap plus I-LV5FU2 across 2 VEGF Trap dose levels (2.0 mg/kg, 4.0 mg/kg) to date. Only 1 dose-limiting toxicity (G3 proteinuria >2 wks with normal plasma creatinine levels) has been encountered so far (4.0 mg/kg, Cycle 2). This pt also had controlled G2 HTN (renal biopsy pending). No other G3/4 VEGF Trap-related AEs have been reported so far. Preliminary free VEGF Trap clearance was 15.4 mL/kg/day. Three pts (synovial sarcoma, ovarian and colon cancers) achieved partial responses. Conclusions: VEGF Trap may be safely combined with I-LV5FU2 at the dose levels studied. Preliminary free VEGF Trap clearance did not differ significantly from that seen with single-agent exposure; chemotherapy PK analysis is pending. The maximum tolerated dose has not yet been reached, and dose escalation continues. Updated safety, pharmacokinetic, and preliminary efficacy results from this ongoing study will be presented. [Table: see text]

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]

Safety and efficacy of AMG 655 plus modified FOLFOX6 (mFOLFOX6) and bevacizumab (B) for the first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4079-4079 ◽  
Author(s):  
L. Saltz ◽  
J. Infante ◽  
L. Schwartzberg ◽  
J. Stephenson ◽  
C. Rocha-Lima ◽  
...  
Keyword(s):  
Disease Progression ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Objective Response ◽  
Death Receptor ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Death Receptor 5 ◽  
Grade 3 ◽  
Ecog Ps

4079 Background: AMG 655 is an investigational fully human monoclonal antibody (IgG1) agonist of human death receptor 5 (DR5). AMG 655 activates caspases and induces apoptosis in sensitive tumor cells. The primary objective of this phase 1b study was to determine the maximum tolerated dose (up to a target dose of 10 mg/kg IV every 2 weeks) of AMG 655 that can be safely administered in combination with mFOLFOX6-B to mCRC pts. Methods: Eligible pts were ≥ 18 years old with previously untreated mCRC, ECOG PS of 0 or 1, and adequate hematologic, hepatic, and renal function. Pts were enrolled into sequential cohorts of 3- or 10-mg/kg AMG 655 + mFOLFOX6-B administered on day 1 of each 14-day cycle. Study endpoints included incidence of dose-limiting toxicities (DLT), adverse events (AE), pharmacokinetic (PK) parameters of AMG 655, and objective response rate (by modified RECIST). Results: As of 09/08, 12 pts (6 per cohort) were enrolled and received ≥ 1 cycle of treatment; 8 were female. Median (range) age was 54 (37–75), median (range) time on AMG 655 treatment was 6.9 (1.6 to 11.4+) months; 8 pts continue on study treatment. There were no DLTs in the first 28 days of treatment. Eight pts had grade 3–4 AE; the most common were diarrhea, febrile neutropenia, peripheral neuropathy, neutropenia, DVT, and pulmonary embolism (2 pts each). Post baseline laboratory parameters grade ≥ 3: no ALT and AST; 1 grade 3 bilirubin (due to disease progression), and 3 grade 3 lipase (asymptomatic). No anti-AMG 655 antibodies were detected. AMG 655 PK values (Cmax, Cmin) were similar to those observed with single-agent AMG 655 (LoRusso JCO 2007; 25: abstract 3534). AMG 655 did not appear to affect PK of oxaliplatin or bevacizumab. Best overall tumor response: 5 partial responses (2 unconfirmed, both underwent resection); 6 stable disease; 1 pt had non-measurable disease at baseline. Time to disease progression (3 patients): 8, 42, and 44 weeks. Conclusions: The addition of AMG 655 does not appear to substantially alter the safety profile of mFOLFOX6-B. The randomized phase 2 part of the trial (mFOLFOX6-B ± AMG 655) is in progress. [Table: see text]

ABT-888 (veliparib) in combination with carboplatin in patients with stage IV BRCA-associated breast cancer. A California Cancer Consortium Trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1010-1010 ◽  
Author(s):  
George Somlo ◽  
Joseph A. Sparano ◽  
Tessa Cigler ◽  
Gini F. Fleming ◽  
Thehang H. Luu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Stage Iv ◽  
Parp Inhibitors ◽  
Maximum Tolerated Dose ◽  
Grade 3 ◽  
The Individual ◽  
Dose Levels ◽  
Better Than

1010 Background: Platinum and PARP inhibitors have both shown activity in BRCA-associated breast cancer (BC) patients (pts). We have conducted a phase I trial of carboplatin (Carb) and velapirib [V], a PARP inhibitor, to define dose limiting toxicities [(DLT) during cycle (C) 1] and the maximum tolerated dose (MTD). Methods: BRCA 1 or 2 carriers with stage IV BC were eligible. Carb starting at an AUC of 6 was given IV every 21 days (length of planned C) and V was administered orally, BID at dose levels (L) L1 through L5 (highest L planned). Results: 22 pts (21 eligible/evaluable, 20 with measurable BC) carrying BRCA1 (10) or BRCA2 (11), or both (1) mutations were accrued. Median age: 45 years, (32-65); 68% of BCs were ER+, and 10% were HER2+. In the table below are the schema, incidence of DLTs, and # of Cs on study. Toxicities: At L1, grade ¾ DLTs with C 1 were seen in 2/6 evaluable pts (1 pt w/grade 3 hyponatremia, pleural effusion, and dehydration, and 1pt w/grade 4 thrombocytopenia [PLT]), leading to deescalation of carb (AUC 5) for pts treated at Ls 2-5. At L2, 1 of 6 pts had grade 4 PLT. There were no DLTs at Ls 3 and L4. L5 is currently being expanded to 6 pts (3 currently enrolled, 1 pt with grade 4 granulocytopenia (Gr) and grade PLT reached DLT). Non-DLT dose delays mostly due ≥ grade 2 Gr or PLT were needed at 60%, 53%, 53%, and 43% of Cs in pts treated on Ls 1-4. Response: In 12 eligible pts treated at Ls 1 and 2, 2 complete and 6 partial responders (67%) and a clinical benefit (CB) of 75% were seen. All pts at Ls 3-5 are still being treated, and in pts treated at Ls 3 and 4, 2 unconfirmed PRs, and 4 cases of stable disease were seen, with L5 too early to assess. Conclusions: The combination of Carb at an AUC of 5 and daily V at doses 150 to 200 mg BID is feasible and the MTD is being defined. In preliminary analysis, response and CB rates are better than expected with the individual agents alone, providing justification to proceed with a planned phase II randomized single agent versus combination trial. [Table: see text]

Phase I trial of sorafenib with concurrent radiotherapy (RT) in patients with invasive bladder cancer treated with bladder-sparing intent: A Spanish Oncology Genitourinary Group study.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 270-270 ◽  
Author(s):  
Juan Martin Liberal ◽  
José Pablo Maroto ◽  
Begoña Mellado ◽  
Ferran Ferrer ◽  
Gemma Sancho ◽  
...  
Keyword(s):  
Phase I ◽  
Clinical Stage ◽  
Complete Response ◽  
Hepatic Function ◽  
High Energy ◽  
Maximum Tolerated Dose ◽  
Bladder Preservation ◽  
Radiation Cystitis ◽  
Grade 3 ◽  
Dose Levels

270 Background: Preclinical studies suggest enhanced radiation-induced cell death when VEGFR inhibitor therapies are combined with RT. Methods: Patients with localized muscle invasive urothelial carcinoma of the bladder in clinical stage T2-3 N0 M0, who were not eligible or rejected radical cystectomy, ECOG PS 0-2, and adequate hematological, renal and hepatic function, were enrolled in this phase I study to assess safety and identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of sorafenib and RT. A 3+3 dose escalation design with cohorts of 3-6 patients was used. Treatment consisted of TUR, followed by normofractionated (2 Gy/day) external-beam RT with high-energy photons, 46 Gy to minor pelvis and 66 Gy to bladder, combined with sorafenib given po continuously. Sorafenib was started two weeks before RT and was administered for 12 weeks, finishing 4 weeks after RT. Dose levels 1, 2 and 3 corresponded to sorafenib 200 mg qd, 200 mg bid and 800 mg bid. Pathological response was assessed by post-treatment TUR. Results: Ten patients were included: median age 71 years (44-84); gender 7M: 3F. Patients were treated at 3 dose levels, the MTD was reached at level 3 and the RD was: sorafenib 200 mg bid with RT. Two DLTs occurred, both at the third dose level: diarrhea grade 3 and digestive bleeding grade 3 with secondary anemia and hemodynamic angor in a patient with previous small bowel angiodysplasia. The most frequent toxicity was diarrhea. Other grade 1-2 toxicities included rash, fatigue, hand-foot syndrome, hypertension, dysuria and urinary frequency. One patient developed late radiation cystitis. Pathological complete response was achieved in 8 of 9 patients evaluated. Salvage cystectomy has been performed in one patient due to recurrent superficial bladder tumor. After a median follow up of 30 months, 6 patients remain disease-free with intact bladder. Conclusions: The combination of sorafenib and RT appears to be feasible and safe allowing long-term bladder preservation in selected patients. A phase II study to assess the activity of this promising combination is warranted.

A phase I study of pazopanib with weekly paclitaxel and carboplatin in advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3021-3021
Author(s):  
Nancy Chan ◽  
Daniella E. Portal ◽  
Rebecca Anne Moss ◽  
Ann W. Silk ◽  
Mark N. Stein ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Unknown Primary ◽  
Weak Inhibitor ◽  
Standard Design ◽  
Proportional Increase ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Levels

3021 Background: Pazopanib (pazo) is an oral tyrosine kinase inhibitor of VEGFR, PDGFR and c-Kit. It is a weak inhibitor of CYP3A4 and CYP2C8 and may decrease paclitaxel (P) clearance. Daily pazo with P and carboplatin (C) every 21 days was not feasible on a previous study. We hypothesized that pazo dosed intermittently and on a different day from P and C may be tolerable. We sought to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of pazo with weekly P and C. Methods: Using a 3+3 standard design, a schedule of P 60-80 mg/m2 and C AUC2 on days 1, 8, and 15 with pazo 400-800 mg on days 2-5, 9-12, and 16-26 on a 28-day cycle was evaluated. Pazo alone could be continued if P and C were omitted due to maximal benefit or toxicity. PK was collected during cycles 1 and 2. Results: 34 patients (pts) were treated over 6 dose levels (Table). Mean age 57 (37-79). Tumor types: breast (22), lung (3) and other (9); 27 had prior platinum. Delay in starting cycle 2 due to grade 3 neutropenia was a DLT at dose level 2 and 5. Pts on 5A missed dosing during C1 and C2 due to neutropenia and required subsequent growth factor, and this was deemed unlikely to be sustainable long-term. All grade toxicities included anemia (62%), neutropenia (59%), and thrombocytopenia (56%). Protocol-defined MTD was not determined. PK analysis showed a dose proportional increase in pazo concentration, consistent with previous reports. Pazo did not alter the PK of C. Cmax of P was higher C2D1 vs C1D1; mean Cmax ratio between C2D1:C1D1 was 1.63 (95% CI:1.29-1.96). There were 11 objective responses (3 CRs, 8 PRs). Five breast pts were on pazo alone for a median of 9 cycles (2-52) with CR (2), PR (2) and SD (1); a squamous cell of unknown primary in CR received 22 cycles. Clinical trial information: NCT01407562. Conclusions: PK confirm that pazo is a weak inhibitor of CYP3A4 and CYP2C8. Myelosuppression was a major adverse event at all dose levels. MTD was not determined. Antitumor activity was achieved with this alternate combination schedule and sustained responses from sequential pazo monotherapy was observed.[Table: see text]

scholarly journals EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
James Leach ◽  
Christine Fuller ◽  
Peter de Blank ◽  
Trent Hummel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
High Grade ◽  
Newly Diagnosed ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

scholarly journals Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Patrick B. Johnston ◽  
Amanda F. Cashen ◽  
Petros G. Nikolinakos ◽  
Anne W. Beaven ◽  
Stefan Klaus Barta ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Dose Intensity ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
T Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Peripheral T Cell Lymphoma ◽  
Grade 3

Abstract Background Belinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL). The primary objective of this study was to determine the maximum tolerated dose (MTD) of belinostat combined with CHOP (Bel-CHOP). Secondary objectives included safety/tolerability, overall response rate (ORR), and belinostat pharmacokinetics (PK). Methods Patients were ≥ 18 years with histologically confirmed, previously untreated PTCL. Patients received belinostat (1000 mg/m2 once daily) + standard CHOP for 6 cycles with varying schedules using a 3 + 3 design in Part A. Part B enrolled patients at MTD dose. Results Twenty-three patients were treated. One patient experienced DLT (Grade 3 non-hematologic toxicity) on Day 1–3 schedule, resulting in escalation to Day 1–5 schedule (n = 3). No DLTs were observed and Day 1–5 schedule with 1000 mg/m2 was declared as MTD. Twelve additional patients were enrolled in Part B using MTD. Median relative dose intensity was 98%. All patients experienced adverse events (AEs), including nausea (78%), fatigue (61%), and vomiting (57%). Serious AEs occurred in 43%, with febrile neutropenia (17%) and pyrexia (13%). Overall ORR was 86% with 71% reported CR at MTD. Belinostat PK parameters were similar to single-agent. Conclusions Bel-CHOP was well tolerated and MTD in CHOP combination was the same dose and schedule as single agent dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT01839097.

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