Phase I Dose-Escalation Trial of Checkpoint Kinase 1 Inhibitor MK-8776 As Monotherapy and in Combination With Gemcitabine in Patients With Advanced Solid Tumors

2015 ◽  
Vol 33 (9) ◽  
pp. 1060-1066 ◽  
Author(s):  
Adil I. Daud ◽  
Michelle T. Ashworth ◽  
Jonathan Strosberg ◽  
Jonathan W. Goldman ◽  
David Mendelson ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Phase I ◽  
Phase Ii ◽  
Ex Vivo ◽  
Dose Intensity ◽  
Median Number ◽  
Qtc Prolongation ◽  
Checkpoint Kinase ◽  
Checkpoint Kinase 1 ◽  
Recommended Phase Ii Dose

Purpose We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies. Patients and Methods Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m2 as monotherapy and then in combination with gemcitabine 800 mg/m2 (part A, n = 26) or gemcitabine 1,000 mg/m2 (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine. Results As monotherapy, MK-8776 was well tolerated, with QTc prolongation (19%), nausea (16%), fatigue (14%), and constipation (14%) as the most frequent adverse effects. Combination therapy demonstrated a higher frequency of adverse effects, predominantly fatigue (63%), nausea (44%), decreased appetite (37%), thrombocytopenia (32%), and neutropenia (24%), as well as dose-related, transient QTc prolongation (17%). The median number of doses of MK-8776 administered was five doses, with relative dose-intensity of 0.96. Bioactivity was assessed by γ-H2AX ex vivo assay. Of 30 patients evaluable for response, two showed partial response, and 13 exhibited stable disease. Conclusion MK-8776 was well tolerated as monotherapy and in combination with gemcitabine. Early evidence of clinical efficacy was observed. The recommended phase II dose is MK-8776 200 mg plus gemcitabine 1,000 mg/m2 on days 1 and 8 of a 21-day cycle.

scholarly journals Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer

2016 ◽  
Vol 34 (15) ◽  
pp. 1764-1771 ◽  
Author(s):  
David Hong ◽  
Jeffrey Infante ◽  
Filip Janku ◽  
Suzanne Jones ◽  
Ly M. Nguyen ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Area Under The Curve ◽  
Primary Objective ◽  
Hair Follicles ◽  
Open Label ◽  
Checkpoint Kinase ◽  
Checkpoint Kinase 1 ◽  
Recommended Phase Ii Dose

Purpose The primary objective was to determine safety, toxicity, and a recommended phase II dose regimen of LY2606368, an inhibitor of checkpoint kinase 1, as monotherapy. Patients and Methods This phase I, nonrandomized, open-label, dose-escalation trial used a 3 + 3 dose-escalation scheme and included patients with advanced solid tumors. Intravenous LY2606368 was dose escalated from 10 to 50 mg/m2 on schedule 1 (days 1 to 3 every 14 days) or from 40 to 130 mg/m2 on schedule 2 (day 1 every 14 days). Safety measures and pharmacokinetics were assessed, and pharmacodynamics were measured in blood, hair follicles, and circulating tumor cells. Results Forty-five patients were treated; seven experienced dose-limiting toxicities (all hematologic). The maximum-tolerated doses (MTDs) were 40 mg/m2 (schedule 1) and 105 mg/m2 (schedule 2). The most common related grade 3 or 4 treatment-emergent adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. Grade 4 neutropenia occurred in 73.3% of patients and was transient (typically < 5 days). Febrile neutropenia incidence was low (7%). The LY2606368 exposure over the first 72 hours (area under the curve from 0 to 72 hours) at the MTD for each schedule coincided with the exposure in mouse xenografts that resulted in maximal tumor responses. Minor intra- and intercycle accumulation of LY2606368 was observed at the MTDs for both schedules. Two patients (4.4%) had a partial response; one had squamous cell carcinoma (SCC) of the anus and one had SCC of the head and neck. Fifteen patients (33.3%) had a best overall response of stable disease (range, 1.2 to 6.7 months), six of whom had SCC. Conclusion An LY2606368 dose of 105 mg/m2 once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC.

The Combination of Quizartinib with Azacitidine or Low Dose Cytarabine Is Highly Active in Patients (Pts) with FLT3-ITD Mutated Myeloid Leukemias: Interim Report of a Phase I/II Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 388-388 ◽  
Author(s):  
Gautam Borthakur ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Low Dose ◽  
Response Rate ◽  
Median Number ◽  
Highly Active ◽  
Flt3 Inhibitor ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Low Dose Cytarabine

Abstract Background: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity. In a phase I and II studies the composite response rate (CRR) was approximately 50% among patients with FLT3-ITD. There is in-vitro synergy between quizartinib and 5-AZA or LDAC. We hypothesize that adding quizartinib to a hypomethylating agent such as 5-azacitidine (AZA) or cytarabine may improve the response rate expected from the use of either agent alone. Objectives: The primary objective of phase I part is to determine the dose limiting toxicity (DLT) and maximally tolerated dose (MTD) of the combination of quizartinib (AC220) with either AZA or low-dose cytarabine (LDAC); for phase II is to determine the clinical activity of both combinations. This planned interim analysis reports on the recommended phase II dose (RP2D) and first futility analysis. Methods: For phase I, patients with relapsed/refractory high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or AML were eligible irrespective of FLT3 mutation and salvage status. For phase II, presence of FLT3-ITD is a requisite. Phase II enrollment is limited to patients >60 years with untreated MDS/CMML/AML, or any age receiving first salvage treatment. Additional eligibilities include performance status ECOG ≤2, adequate organ function, normal electrolytes (potassium, calcium and magnesium). Important exclusions include QTcF> 450 mSec, concomitant drugs that prolong QT/QTc interval or strong CYP3A4 inhibitors or inducers with the exception of antibiotics, antifungals, and antivirals that are used as standard of care. Treatment cycle is defined as 28 days. Treatment comprises of AZA 75 mg/m2 subcutaneously (SQ) or intravenously (IV) for 7 days of every cycle (Days 1-7), or cytarabine 20 mg SQ twice daily for 10 days of every cycle (Days 1-10) along with quizartinib at two planned dose levels: 60 mg (dose level 1) or 90 mg orally daily (dose level 2) uninterrupted. Patients are assigned to AZA or LDAC arm by physician choice or slot availability. Planned accrual for each arm in phase 2 is 26 pts each and an ORR of ≥50% will be considered favorable. Accrual of 26 pts will give a 95% credible interval for overall response rate of (0.32, 0.68). The study will be stopped for toxicity (>30%) and/or futility (ORR <50%) at interim analysis for each arm. Results: Twenty-six (Phase I=12, phase II=14) pts have been enrolled: 18 to AZA arm and 8 to LDAC arm. Median age is 62 years (range, 25-79 years), 7 (27%) are female. Cytogenetics are diploid=14, +8=2, -7=2, miscellaneous=6, 11q and t(8;21)= 1 each. Median number of prior therapies is 2 (range, 0-7), 7 patients received prior FLT3 inhibitor. For both schedules quizartinib 60 mg daily was identified as the recommended phase II dose (RP2D) based on emerging results from separate dose-finding study. Eighteen [5 in LDAC arm (63%) and 13 (72%) in AZA arm; all with FLT3-ITD mutation without D835 mutation] of 26 total pts (69%) have responded (CR=1/ CRp=3/ CRi=2/ MLFS=10/PR=1/HI=1). Among patients with FLT3-ITD (N=22), ORR is 82%. Four of 7 (57%) patients with prior FLT3 inhibitor exposure responded. Median number of days to respond is 57 days (range, 25-102 days). Among responders two patients died (MLFS=1, PR=1): one with gastro-intestinal bleeding and other with progressive pneumonia. Three additional responders have discontinued therapy for stem cell transplant (1), withdrawal of consent (1), and loss of response with emergence of D835 mutation (1). Nine responders (CR=1, CRi=1, CRp=1, PR=1, MLS=5) had >50% reduction of FLT3-ITD allelic burden and 2 additional pts (CR=1, CRi=1) had no detectable FLT3-ITD at response. Number of pts with treatment emergent grade 3/4 toxicities irrespective of attribution include hypokalemia (15), hypophosphatemia (5), hyponatremia (4), hypocalcemia (4), hyperbilirubinemia (3), increase in ALT (1), hypernatremia (1hyperglycemia (1), hypotension (1), QTcF prolongation (1, grade 3). Conclusion: Combination of quizartinib and AZA or LDAC is highly active among patients with AML/MDS/CMML with FLT3-ITD . Response rates appear higher than expected with either agent alone. Clinically significant QTcF prolongation is infrequent. Accrual to both arms of the current trial continues. Disclosures Cortes: Ambit Biosciences: Research Funding.

Phase I/II docetaxel, oxaliplatin, and 5-fluorouracil combination chemotherapy in patients with advanced gastric cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 162-162
Author(s):  
Sung Rok Kim ◽  
Sung-En Park ◽  
Young Jin Yuh ◽  
Byeong Seok Sohn ◽  
Hye Ran Lee ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Advanced Gastric Cancer ◽  
Phase Ii ◽  
Combination Chemotherapy ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

162 Background: The results of recent studies with duo- or triple regimen for the advanced gastric cancer are still not satisfactory and the optimal doses of combinations with taxanes, fluorouracil and platinum analogues were not determined yet. The aim of this study is to determine the optimal dose of docetaxel and oxaliplatin in combination with 5-fluorouracil(FU) [DOF], with the efficacy and toxicity in patients (pts) with advanced gastric cancer. Methods: The pts with unresectable, metastatic, or relapsed gastric cancer were enrolled for a phase I/II study. The dose of docetaxel and oxliplatin was escalated from 50 mg/m2 and 80 mg/m2 day 1, respectively by traditional 3+3 design, and 5-FU was fixed at 850 mg/m2/day 24 hour continuous infusion day 1-4, all every 3 weeks. All pts had measurable disease and were assessable for toxicity. Results: A total of 50 pts including 12 patients from phase I study were enrolled. The recommended phase II dose of docetaxel and oxaliplatin were 60mg/m2 and 100mg/m2 on day 1 (cohort 2), respectively. A total of 335 cycles of chemotherapy was administrated (median: 6, range 1–24) and the dose intensity of docetaxel, oxaliplatin, and 5-FU were 96.3%, 96.2% and 98.5%, respectively. Twenty two (44.0%) of 50 patients showed partial response, 22 (44.0%) stable disease, and 1 (2.0%) complete response. The overall response rate was 46.0% (95% confidence interval [CI]: 32.2–60.0%) and the disease control rate 90.0% (95% CI: 81.7–98.3%). The median progression free survival was 6.5 months (95% CI, 3.3–9.8) and the overall survival 10.7 month (95% CI, 7.0–14.3). Grade 3/4 neutropenia and thrombocytopenia occurred in 81 (24.1%) and 3 cycles (0.9%), respectively [27 (56%) and 3 (6%) in 50 pts, respectively]. Grade 3/4 stomatitis, diarrhea and neuropathy occurred in 2 (0.6%), 6 (1.8%) and 6 cycles (5.7%), respectively. Conclusions: The recommended phase II dose of docetaxel and oxaliplatin was 60mg/m2 and 100mg/m2, respectively. This DOF combination chemotherapy has no better efficacy than reference regimen. The toxicities were substantial in some pts, but generally manageable.

scholarly journals Analysis of the ex-vivo transformation of semen, saliva and urine as they dry out using ATR-FTIR spectroscopy and chemometric approach

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tanurup Das ◽  
Abhimanyu Harshey ◽  
Ankit Srivastava ◽  
Kriti Nigam ◽  
Vijay Kumar Yadav ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Ex Vivo ◽  
Body Fluids ◽  
Biochemical Changes ◽  
Partial Least Square ◽  
The Body ◽  
Slow Phase ◽  
Time Since Deposition ◽  
Dry Out

AbstractThe ex-vivo biochemical changes of different body fluids also referred as aging of fluids are potential marker for the estimation of Time since deposition. Infrared spectroscopy has great potential to reveal the biochemical changes in these fluids as previously reported by several researchers. The present study is focused to analyze the spectral changes in the ATR-FTIR spectra of three body fluids, commonly encountered in violent crimes i.e., semen, saliva, and urine as they dry out. The whole analytical timeline is divided into relatively slow phase I due to the major contribution of water and faster Phase II due to significant evaporation of water. Two spectral regions i.e., 3200–3400 cm−1 and 1600–1000 cm−1 are the major contributors to the spectra of these fluids. Several peaks in the spectral region between 1600 and 1000 cm−1 showed highly significant regression equation with a higher coefficient of determination values in Phase II in contrary to the slow passing Phase I. Principal component and Partial Least Square Regression analysis are the two chemometric tool used to estimate the time since deposition of the aforesaid fluids as they dry out. Additionally, this study potentially estimates the time since deposition of an offense from the aging of the body fluids at the early stages after its occurrence as well as works as the precursor for further studies on an extended timeframe.

Tibial Tuberosity Transposition Fixation with a Locking Plate during Medial Patellar Luxation Surgery: An Ex Vivo Mechanical Study

2021 ◽  
Author(s):  
Esa V. Eskelinen ◽  
Ari P. Suhonen ◽  
Juha V. Virolainen ◽  
William D. Liska
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Locking Plate ◽  
Ex Vivo ◽  
Tibial Tuberosity ◽  
Tension Band ◽  
Patellar Ligament ◽  
Raccoon Dog ◽  
Tension Band Wire ◽  
Lower Load

Abstract Objectives The purpose of this study was to compare the load at failure, stiffness and mode of failure between three types of tibial tuberosity transposition fixation techniques: (a) pin and figure-8 tension band wire (Pin-TBW), (b) locking plate with pin and a tension band wire (Plate-Pin-TBW) and (c) locking plate with a pin (Plate-Pin). Methods Six pairs of raccoon dog cadaveric tibiae were tested in Phase I Pin-TBW versus Plate-Pin-TBW and seven pairs in Phase II Plate-Pin-TBW versus Plate-Pin. One limb of each pair was randomly assigned to one of two groups for each phase. A tensile force was applied to the patellar ligament until construct failure. Results Pin-TBW (342N ± 54.7N) failed at a lower load than Plate-Pin-TBW (469N ± 77.3N), p = 0.00748, with all Pin-TBW failing by fracture and the majority of Plate-Pin-TBW failing by rupture of patellar ligament. Pin-TBW group Phase I, normalized with Plate-Pin-TBW Phase I, failed at a lower load than Plate-Pin group Phase II, normalized with Plate-Pin-TBW Phase II, p = 0.00467. There was no significant difference in mean load at failure, stiffness or mode at failure between the groups in the Phase II study. Clinical Significance Although ex vivo mechanical testing does not replicate the postoperative live dog or cat, these results demonstrate lower construct strength of the Pin-TBW construct compared with the Plate-Pin construct in the raccoon dog cadaver model.

Preliminary Results of a Phase I/II Trial of BBR-2778 (Pixantrone) in Combination with Fludarabine, Dexamethasone, and Rituximab (FPD-R) in the Treatment of Patients with Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma (NHL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1324-1324 ◽  
Author(s):  
Luis Fayad ◽  
James Liebmann ◽  
Manuel Modiano ◽  
Gary I. Cohen ◽  
Barbara Pro ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase Ii ◽  
Performance Status ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Outpatient Basis ◽  
Significant Activity ◽  
Cardiac Events

Abstract Background: Fludarabine-mitoxantrone-dexamethasone-rituximab (FND-R) is a combination chemotherapy with significant activity in untreated and relapsed indolent B-cell lymphoma patients (pts). Pixantrone is a novel aza-anthracenedione that has no delayed cardiotoxicity in animal models and has single agent activity in NHL. We conducted an outpatient phase I/II trial, to define the recommended dose (RD) of pixantrone when substituting for mitoxantrone in the FND-R regimen, and the safety and efficacy of this regimen in pts with relapsed or refractory indolent NHL. Methods: Pts received pixantrone with fludarabine (25mg/m2/day, days 1–3), dexamethasone (20mg/day, days 1–5), and rituximab (375mg/m2/day on day 1) in a 28 day regimen (FPD-R). Based on previous single agent clinical studies, the starting dose of pixantrone was defined as 80mg/m². The RD was established to be 120mg/m2 and the protocol was amended to treat patients in the phase II part. Results: 9 pts (6 males) with a median age of 65 years (range 41–78) were included in the dose-finding part of the study. Following the protocol amendment, 23 pts (11 males) of WHO performance status 0–1, median age 61 (range 32–78) have been enrolled in the currently ongoing phase II part. Pathology included SLL/CLL, follicular grade I, follicular grade II, MALT, marginal cell, and other indolent B-cell lymphomas. All pts had received a prior anthracycline-containing regimen (median number 1, range 1–4). The study regimen was well tolerated; median number of courses received was 5 (range 2–8). Grade 4 toxicities were neutropenia in 10 pts, leukopenia in 5 pts, and thrombocytopenia in 1 pt. No clinically significant cardiac events or decreases in LVEF ≥20% were noted. However 4 pts went below 50% LVEF including 1 pt who was below 50% at baseline. Non-hematologic adverse events were primarily grade 1 or 2 in severity. Response rate was 75% for the 20 pts evaluable for response, with 11 (55%) complete remission [7 confirmed (CR), 4 unconfirmed (CRu)], and 4 (20%) partial remission (PR). Two responders went onto bone marrow transplant (BMT): one had a CRu and one a PR. A third patient was pending BMT after CR. At a median follow-up of 345 days, the median duration of response has not been reached, as only two pts have progressed: the first progression occurred at 113 days, and the second pt progressed at 699 days. The remaining pts are still in remission. Conclusions: The RD of pixantrone in the FPD-R regimen is 120mg/m2. The primary toxicity is hematologic. The regimen can be given on an outpatient basis, is associated with major responses, and is very well tolerated in relapsed and refractory indolent NHL pts.

Reversion of Chemoresistance in Aggressive Lymphoma by Quinine. A Phase II Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4572-4572
Author(s):  
Pierre Soubeyran ◽  
Amine Masmoudi ◽  
Christele Blanc-Bisson ◽  
Isabelle Soubeyran ◽  
Ricardo Bellott ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Cell Lymphoma ◽  
Previous History ◽  
Dose Intensity ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Aggressive Lymphoma ◽  
History Of ◽  
Resistance To Chemotherapy

Abstract Multidrug resistance has been one of the most studied mechanisms of cancer cell resistance to chemotherapy. Evidence of its involvement in hematological malignancies is known since many years. One well-designed phase I trial showed that about 20 to 25% of patients strictly resistant to EPOCH schedule could become responsive again by the addition of Dex-verapamil (J Clin Oncol1995; 13:1995–2004). We decided to perform a phase II trial to evaluate whether quinine could reverse resistance to chemotherapy in aggressive lymphoma. Methods: Patients included had all received at least two lines of chemotherapy including CEOP (cyclophosphamide 750mg/m2, epirubicine 60mg/m2, vincristine 1.4mg/m2 IV day 1 and prednisone 40mg/m2 orally day1 to day 7) and were demonstrated as strictly refractory to CEOP i.e. either no change or progression. Q-CEOP was administered as follows: quinine 30-mg/kg/day for two days from d0 to d1 as a continuous infusion, CEOP at the beginning of d1. Results: 15 patients have been included with the following characteristics: median age: 52 years (32–64), 66% stage III–IV, 60% elevated LDH. The median number of previous regimens was 3 (2–5). 13 patients had diffuse large B cell lymphoma including 3 with previous history of follicular lymphoma. Two had mantle cell lymphoma. Seven patients were included directly since they were initially refractory to CEOP while eight were shown refractory after two further cycles of CEOP. Epirubicin pharmacokinetics was not influenced by quinine. Mean dose intensity of epirubicin was 94%. Toxicity was mild. 4 responses were observed at the end of treatment including 2 complete and 2 partial responses (26%, IC 95%: 8–55%). Only the 2 CR patients are still alive with no evidence of disease at 35+ and 61+ months. Conclusion: These results add further arguments to confirm that MDR1 plays a significant role in resistance to chemotherapy in lymphoma. Quinine allowed unexpected long term remission in 2 responding patients.

High Dose Zevalin (90Yttrium Ibritumomab Tiuxetan) Treatment with PBSC Support in Refractory-Resistant NHL Patients: Preliminary Results of a Phase I/II Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 488-488 ◽  
Author(s):  
Anna Vanazzi ◽  
Pierfrancesco Ferrucci ◽  
Mahila Ferrari ◽  
Liliana Calabrese ◽  
Marta Cremonesi ◽  
...  
Keyword(s):  
Phase I ◽  
Median Time ◽  
Dose Intensity ◽  
Median Number ◽  
Therapeutic Options ◽  
Clinical Activity ◽  
High Dose ◽  
Resistant Refractory ◽  
Duration Of Response ◽  
Heavily Pretreated

Abstract Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT or for those pts relapsing after ABMT. Zevalin has been already demonstrated active in elderly pts with resistant-primary refractory DLBCL at dose of 0.4 mCi/kg, however duration of response is short. Increasing RIT dose intensity might improve efficacy. There are no data about the use of Zevalin at myeloablative dosage. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. Three Zevalin dose-levels were fixed: 0.8, 1.2, 1.5 mCi/kg; from April 2004 to July 2005 12pts were enrolled, 4pts at each dose level. Median age was 66,5 ys (28–73), 83% male. All pts had stage III/IV at diagnosis; 7DLBCL; 3MCL, 1FL, 1transformed MZL. 7pts had received more than 3 previous CT regimens. All pts had received prior rituximab, 3pts RT, 6pts HD-CT. BM was negative in all pts before RIT. 1Week prior to Zevalin all pts underwent dosimetry and if no abnormal uptake was observed they received the planned dose. On Day −7 and 0 imaging and therapeutic doses were preceded by rituximab 250mg/mq. On Day13 pts were reinfused with PBSC previously harvested. On Day28 from reinfusion engraftment was considered to be delayed if WBC/ANC were&lt;1.0x109/L or PLT&lt;20x109/L. All pts engrafted promptly after PBSCT with median time to WBC/ANC&gt;1.0x109/L and PLT&gt;20x109/L of 19 (range 0–23) and 12 days (0–22) from PBSCT. PLT and ANC count nadirs were observed at 21 (0–24) and 25 (0–31) days after Zevalin with median values of 11x109/L(4–35) and 0.24x109/L(0.01–1.09). Median time to recovery from nadir was 16,5 days (4–175) for PLT and 17days (7–175) for ANC. 8pts required PLT transfusions, 4pts RBC transfusions; median number of PLT transfusions:1(1–4). No G-CSF was administered. No significant differences in terms of haematologic toxicity were observed among the 3 levels. No pulmonary, renal or cardiac toxicity was observed. 11/12 pts are now evaluable for response: 5pts experienced a CR (2 at 0.8mCi/kg, 2 at 1.2mCi/kg, 1 at 1.5mCi/kg), 1 pt receiving 1.5 mCi/kg a PR (ORR 50%); to date 4 pts maintain CR at 12, 11, 9 and 8 months after treatment. Conclusion: Zevalin at dosage higher than MTD is feasible with PBSC support. Even at dosage 4 times higher than standard, HD-Zevalin could be safely delivered in elderly and heavily pretreated pts, including those who previously received HD-CT. Clinical activity and mild treatment-related toxicities suggest that HD-Zevalin is an interesting modality treatment to be further investigated as an alternative therapeutic options for resistant-refractory NHL.

Clofarabine (CLO) Has Single Agent Activity in Relapsed and Refractory Non-Hodgkin Lymphoma (NHL) Including Rituximab (R)-Refractory Patients (pts).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 921-921
Author(s):  
Chadi Nabhan ◽  
Jacob David Bitran ◽  
Walter Fried ◽  
Angel G. Galvez ◽  
Laura Magid ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Large Cell ◽  
Median Number ◽  
Low Grade ◽  
Grade 3

Abstract Abstract 921 Background: CLO is a second generation nucleoside analogue with known activity in acute leukemia and myelodysplasia. As there is no standard therapy for refractory and transplant-ineligible relapsed NHL, and given the activity that purine analogues have in lymphoid malignancies, we sought to investigate the activity of CLO in this pt population regardless of histology. Methods: Eligible pts had measurable disease by CT and/or PET, ECOG performance status ≤ 2, and adequate renal, cardiac, liver, and bone marrow function (unless cytopenias were disease-related). CLO was given in the outpatient setting intravenously over 1-hour days 1-5 every 28 days for 6 cycles maximum. All pts received anti-viral and anti-pneumocystis jiroveci prophylaxis. First, we initiated a phase I portion using a standard 3×3 study design. CLO was given at 4 mg/m2 in cohort 1 with subsequent cohorts to be escalated by 2 mg/m2 each. Once the maximum tolerated dose (MTD) was determined, the phase II portion of this study was initiated at the MTD. All pts were followed until disease progression. Results: Thirty-three pts (18 females, 15 males) have been enrolled (7 in the phase I portion and 26 in the phase II), of which 29 are evaluable for response and/or toxicity (2 just started therapy, 1 taken off due to persistent cytopenias, and 1 withdrew consent). Median age was 69 years (range 27-88), median number of prior therapies was 3 (range 1-8), with 21% failing prior stem cell transplantation and 74% being R-refractory. Median time from original diagnosis to first CLO treatment was 36 months (range 6-216). Histologies included 12 diffuse large cell, 5 follicular, 5 small lymphocytic, 4 anaplastic large T-cell, and 1 each for Richter, mantle cell, marginal zone, peripheral T-cell, transformed, non-specific T-cell, and mixed histology. Median number of CLO cycles was 4 (range 1-6). Thrombocytopenia was the dose-limiting toxicity at 6 mg/m2 in 2/6 pts. The MTD recommended for phase II was 4 mg/m2. With a median follow up of 8 months (range 1-33), 7 pts (24%) showed complete response (CR) and 8 (27%) had partial response (PR) for an overall response rate of 51%. Four pts (13%) demonstrated stable disease and 10 (34%) showed progression. Median duration of response was 7 months (range 2-33+) with 6 pts continuing in remission including a patient who is undergoing stem cell transplantation. Median time to progression (TTP) was 3.5 months with median overall survival of 8 months. sEVEN pts (24%) remain progression-free. Of patients who were followed for more than 12 months, 60% were alive at 1-year. Five of the CR pts were of low-grade histology while only 2 had large cell lymphoma. All pts required growth factor support. Toxicity was mainly hematologic with 63% experiencing grade 3/4 thrombocytopenia, 60% grade 3/4 neutropenia, and 39% grade3/4 anemia, and 63%. Grade 3 and/or 4 non-hematologic toxicity included 2 (6%) with tumor lysis syndrome, 2 (6%) infectious episodes (pneumonia and bilateral cellulitis), 2 (6%) renal insufficiency, 2 (6%) fatigue, 1 (3%) seizure activity, 1 (3%) pleural effusion, and 1 hypokalemia (3%). No treatment-related mortality. Conclusions: CLO is active in heavily pre-treated B-cell NHL including R-refractory pts. Activity appears more pronounced in low-grade histology. The drug is well-tolerated and can be administered as an outpatient. Reversible myelosuppression is the major toxicity. Future studies in front-line in combination with R are warranted. Disclosures: Nabhan: Bayer: Honoraria, Research Funding, Speakers Bureau; Genzyme: Research Funding; Genentech: Honoraria, Speakers Bureau. Venugopal:Genzyme: Honoraria, Research Funding; Genentech: Honoraria, Research Funding, Speakers Bureau.

The Combination of Quizartinib with Azacitidine or Low Dose Cytarabine Is Highly Active in Patients (Pts) with FLT3-ITD Mutated Myeloid Leukemias: Interim Report of a Phase I/II Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1642-1642 ◽  
Author(s):  
Waleed Abdelall ◽  
Hagop M. Kantarjian ◽  
Gautam Borthakur ◽  
Guillermo Garcia-Manero ◽  
Keyur P. Patel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Low Dose ◽  
Response Rate ◽  
Highly Active ◽  
Flt3 Inhibitor ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Low Dose Cytarabine

Abstract Background: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with early relapse and poor survival. Quizartinib inhibits FLT3 kinase activity potently and selectively. In phase I and II studies, the composite response rate (CRR) was approximately 50% among patients with FLT3-ITD. There is in-vitro synergy between quizartinib and 5-AZA or LDAC. We hypothesize that adding quizartinib to a hypomethylating agent- such as 5-azacitidine (AZA) -or to cytarabine may improve the response rate expected from the use of either agent alone. Objectives: The primary objective of phase I is to determine dose limiting toxicity (DLT) and maximally tolerated dose (MTD) of combination of quizartinib with either AZA or low-dose cytarabine (LDAC); for phase II is to determine the clinical activity of both combinations. This planned interim analysis reports on the recommended phase II dose (RP2D) and first futility analysis. Methods: For phase I, pts with relapsed/refractory high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or AML were eligible irrespective of FLT3 mutation and salvage status. For phase II: presence of FLT3-ITD is a requisite, pts must be >60 years with untreated MDS/CMML/AML or any age receiving first salvage treatment. Other requisites: performance status ECOG ≤2, adequate organ function and normal electrolytes (potassium, calcium and magnesium). Important exclusions include: QTcF> 450 msec, administration of drugs that prolong QT/QTc interval or strong CYP3A4 inhibitors or inducers; with the exception of antibiotics, antifungals, and antivirals that are used as standard of care. Treatment cycle is 28 days and comprises of AZA 75 mg/m2 subcutaneously (SQ) or intravenously (IV) for 7 days of every cycle, or cytarabine 20 mg SQ twice daily for 10 days of every cycle along with quizartinib at two planned dose levels: 60 mg (dose level 1) or 90 mg orally daily (dose level 2), uninterrupted. Patients are assigned to AZA or LDAC arm by physician choice or slot availability. Planned accrual for each arm in phase II is 26 pts each and an ORR of ≥50% will be considered favorable. Accrual of 26 pts will give a 95% credible interval for ORR of (0.32, 0.68). The study will be stopped for toxicity (>30%) and/or futility (ORR <50%) at interim analysis for each arm. Results: Fifty-two (Phase I=12, phase II=40) pts have been enrolled: 38 to AZA arm and 14 to LDAC arm. Median age is 67 years (range, 23-83 years), 24 (46%) are female. Cytogenetics are diploid=24, +8=5, monosomy 7=3, miscellaneous=17, 11q=2 and t(8;21)= 1. Median number of prior therapies is 1 (range, 0-7); 7 patients had received prior FLT3 inhibitor: sorafenib (5), crenolanib (1), quizartinib (1). For both combinations quizartinib 60 mg daily was identified as the recommended phase II dose (RP2D). Thirty-five Pts [8 in LDAC arm (23%) and 27 in AZA arm (77%)] of total 52 have responded with ORR 67 % (CR=8, CRp=7, CRi=18, PR=2); all with FLT3-ITD mutation without D835 mutation. ORR is 73% among pts with FLT3-ITD (N=48). Three of eight pts (38%) with prior FLT3 inhibitor exposure responded. Median time to response is 35 days (range, 14-187days). Among responders, two pts died (in CRi=1, PR=1): one with GI bleed and one with progressive pneumonia. Twelve responders discontinued therapy: 11 to receive a SCT and 1 due to loss of response with emergence of D835 mutation. Fifteen responders (CR=2, CRi=8, CRp=3, PR=2) had >50% reduction of FLT3-ITD allelic burden and eight additional pts (CR=5, CRi=1, CRp=2) had no detectable FLT3-ITD at response. The median survival was: 14.8 mo for the total study group: 7.5 mo for LDAC arm and not reached for AZA arm; median EFS has not been reached for either arm (Figure). Treatment emergent grade 3/4 toxicities irrespective of attribution include hypokalemia (15), hypotension (7), hypophosphatemia (7), hyponatremia (7), hypocalcemia (7), hyperbilirubinemia (1), elevated ALT (5), hypernatremia (2) hyperglycemia (1), QTcF prolongation (1, grade 3). Conclusion: Combination of quizartinib and AZA or LDAC is highly active among patients with AML/MDS/CMML with FLT3-ITD mutation in absence of D835 mutation. Response rates appear higher than expected with either agent alone. Clinically significant QTcF prolongation is infrequent. Accrual to the study continues. Figure Figure. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

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