Dose-escalation trial of cladribine using five daily intravenous infusions in patients with advanced hematologic malignancies.

1996 ◽  
Vol 14 (1) ◽  
pp. 188-195 ◽  
Author(s):  
R A Larson ◽  
R Mick ◽  
R T Spielberger ◽  
S M O'Brien ◽  
M J Ratain
Keyword(s):  
Platelet Count ◽  
Dose Escalation ◽  
Performance Status ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Dose Escalation Study ◽  
Intravenous Infusions ◽  
Drug Concentrations ◽  
Nonhematologic Toxicity

PURPOSE The optimal dose and schedule for cladribine (2CdA) therapy of malignant hematologic diseases have not been determined. This dose-escalation study was designed to assess toxicity when 2CdA is given using five daily 1-hour intravenous infusions. PATIENTS AND METHODS Forty-two adults with advanced hematologic malignancies were treated in one of nine cohorts, starting at 2.5 mg/m2/d for 5 days. Plasma drug concentrations were measured by high-performance liquid chromatography. Responses were assessed by bone marrow biopsy on day 15 of the first course and by clinical measurements after each course. Patients received one to four courses each. RESULTS Nonhematologic toxicity was mild, and dose-limiting nonhematologic toxicity was not observed, even at the highest dose level of 21.5 mg/m2/d. In particular, neurotoxicity was not observed. The maximum-tolerated dose (MTD) was not identified. However, prolonged cytopenias and severe infections were more common in the higher 2CdA dose cohorts. Logistic regression analysis suggested that severe hematologic toxicity was associated with pretreatment platelet count and performance status (PS). Good-risk patients were identified as having a PS of 0 and platelet count > or = 80,000/microL, PS of 1 and platelet count > or = 120,000/microL, or PS of 2 and platelet count > or = 160,000/microL. Sustained complete responses (CRs) and partial responses (PRs) were observed in eight patients. CONCLUSION 2CdA can be administered using five daily 1-hour infusions at 21.5 mg/m2/d without dose-limiting nonhematologic toxicity. Unlike continuous intravenous infusions, neurotoxicity was not observed using this schedule. Further dose escalation may be possible in good PS patients with adequate platelet counts.

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, 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 .

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.

Results of a Phase I Study of GRN163L, a Direct Inhibitor of Telomerase, in Patients with Relapsed and Refractory Multiple Myeloma (MM)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3688-3688 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Nikhil C. Munshi ◽  
Mohamad A. Hussein ◽  
Laurence Elias ◽  
Fabio Benedetti ◽  
...  
Keyword(s):  
Phase I ◽  
Telomere Length ◽  
Dose Escalation ◽  
Plasma Concentrations ◽  
Clinical Signs ◽  
Telomerase Activity ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Hematologic Toxicity ◽  
Dose Escalation Study

Abstract Telomerase over-expression is the predominant mechanism by which cancer cells maintain adequate telomere length to achieve immortalization. Telomere length is often decreased and telomerase activity is often increased in MM. GRN163L is a 13-mer oligonucleotide that directly inhibits telomerase activity and has demonstrated anticancer effects in various preclinical models. We are conducting a phase I dose escalation study to define the maximum tolerated dose (MTD), safety, tolerability, efficacy as well as pharmacokinetics of GRN163L in patients with relapsed or refractory MM. Each treatment cycle consisted of 3 weekly 2 hr i.v. infusions of GRN163L. Dose escalation followed standard “3+3” dose finding rules. To date, 12 patients, median age 61 years, have been treated in 3 dose cohorts (3.2, 4.8 and 7.2 mg/kg). Patients had received a median of 4.0 prior treatment regimens. All patients had normal baseline neutrophil and 10 had normal baseline platelet counts. Patients completed a median of 2 cycles of GRN163L treatment, with one receiving 4 and another 6 cycles. GRN163L has been generally well-tolerated to date. One patient had Gr 3 anorexia however all other related or possibly related non-hematologic AEs to date were Gr 1 or 2. Treatment related events included thrombocytopenia, neutropenia, aPTT prolongation, anemia, fatigue, nausea, anorexia, and dizziness. No dose limiting toxicity (DLT) occurred among patients in the first 2 cohorts. All patients exhibited transient dose-related aPTT prolongations, which resolved in parallel with decreasing GRN163L plasma levels. There were no bleeding episodes or clinical signs of complement activation. Two of the 5 patients in the 7.2 mg/kg cohort had transient prolongation of aPTT to > 3 fold of the upper limit of normal. One patient in the highest dose group had Gr 4 thrombocytopenia in Cycle 1, which constituted a DLT. Delayed (cycle 2 or later) Gr 3 or 4 neutropenia or thrombocytopenia was noted in 5 additional patients with no episodes of febrile neutropenia. Maximal post-infusion plasma concentrations (Cmax) of GRN163L have been linear with respect to dose. Mean (± SD) plasma concentration of GRN163L declined by 41.1 ±17.6 %, N=9, over the 2 hours following the first infusion, consistent with other previously reported studies. DLTs observed in this study were thrombocytopenia and aPTT prolongation. The MTD for continuous weekly dosing of GRN163L in this heavily pretreated, relapsed and refractory MM population appears to be ≥ 4.8 and < 7.2 mg/kg. The most marked hematologic toxicity was observed in two patients with prior autologous stem cell transplantation. Exploration of intermediate dose levels in this range is continuing. Additional studies exploring alternative dosing schedules will be initiated.

Phase I dose-escalation study of novel oral multi-target tumor growth inhibitor (MTGI) ZK 304709 administered daily for 7 days of a 21-day cycle to patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2073-2073 ◽  
Author(s):  
J. Graham ◽  
K. Wagner ◽  
R. Plummer ◽  
B. Wiedenmann ◽  
J. Cassidy ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Oral Delivery ◽  
Performance Status ◽  
Dose Range ◽  
Systemic Exposure ◽  
Growth Inhibitor ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Refractory Solid Tumor

2073 Background: ZK304709 is a novel MTGI that selectively inhibits activity of Cyclin Dependent Kinases (CDKs) 1, 2, 4, 7, 9, and the tyrosine kinase activity of VEGF-R 1, 2, 3 and PDGF-βR. Methods: Adult patients (pts) with a good performance status (WHO PS ≤2) and a histologically or cytologically confirmed relapsed/refractory solid tumor were eligible. ZK304709 is administered, as a monotherapy, orally on days 1–7 of a 21-day cycle to fasting patients at a starting dose of 15 mg qd. Dose escalation has ranged from 33% - 100% of prior dose, depending on occurrence of drug-related toxicity ≥ grade (gr) 2 (CTC v2.0). Between 3 and 7 patients are to be enrolled per dose level, depending on DLTs that are observed. The primary objective is determination of the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of ZK304709. Secondary objectives include tolerability, pharmacokinetic (PK) profile, and preliminary efficacy. Results: Interim results are available for 22 pts (15 M/7 F, median age 60.5 yrs; range 37–71) treated with ZK304709 at 6 dose levels (15 - 180 mg qd). Patients completed a median of 2 cycles (range 0–8). Common AEs were nausea, vomiting, diarrhea, and lethargy. Two DLT were observed: supraventricular tachycardia and vomiting, but the MTD was not reached. The PK profile shows rapid absorption, with a Tmax of 2–4 hrs, and a dose-dependent increase in systemic exposure over the 15–90 mg dose range. Disease stabilization for ≥4 cycles has been observed. Conclusions: ZK304709 is rapidly absorbed and has been tolerated on this schedule at doses up to 180 mg qd. The MTD has not been reached, and enrolment is ongoing. These preliminary data demonstrate that oral delivery on this schedule of an agent that inhibits both cell cycle and angiogenesis is feasible. [Table: see text]

Effective Dosing of Topotecan With Carboplatin in Relapsed Ovarian Cancer: A Phase I/II Study

2001 ◽  
Vol 19 (13) ◽  
pp. 3255-3259 ◽  
Author(s):  
A. Bowman ◽  
T. Rye ◽  
G. Ross ◽  
A. Wheatley ◽  
J. F. Smyth
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Nonhematologic Toxicity ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3 ◽  
Carboplatin Auc

PURPOSE: This phase I/II study was performed to evaluate the feasibility of administering the topoisomerase inhibitor topotecan in combination with carboplatin. PATIENTS AND METHODS: Topotecan was given as a 30-minute infusion daily for 5 days, with carboplatin given immediately after topotecan on day 5. Treatment was repeated every 21 days. Carboplatin and then topotecan were escalated in sequential cohorts of three to six patients. Four dosage combinations of topotecan days 1 to 5 and carboplatin (day 5) were tested: 0.5 mg/m2/d and carboplatin area under the curve (AUC) of 4, topotecan 0.5 mg/m2/d and carboplatin AUC of 5, topotecan 0.75 mg/m2/d and carboplatin AUC of 5, and topotecan 1.0 mg/m2/d and carboplatin AUC of 5. RESULTS: Grade 3 and 4 neutropenia was common at doses of 0.75 mg/m2/d and above, but dose-limiting hematologic toxicity occurred in only one patient. The most common reason for dose reduction or delay was failure of myelosuppression to resolve by day 21. Nonhematologic toxicity was generally mild. The maximum-tolerated dose as defined in the protocol was not reached, but topotecan dose escalation was stopped at 1.0 mg/m2/d, because delayed neutrophil recovery precluded re-treatment on a 21-day schedule. CONCLUSION: Hematologic toxicity was common but rarely serious, and the combination of topotecan with carboplatin on this schedule was safe and well tolerated. Giving carboplatin to patients after topotecan on day 5, rather than on day 1, allowed dose escalation beyond the levels reported in other studies. The recommended doses for previously treated patients are topotecan 0.75 mg/m2/d, days 1 to 5, with carboplatin at an area under the curve (AUC) of 5 following topotecan on day 5. The combination of topotecan 1 mg/m2/d, days 1 to 5, followed on day 5 by carboplatin at an AUC of 5, merits further examination in untreated patients.

scholarly journals Effective Dosing of Topotecan with Carboplatin in Relapsed Ovarian Cancer

2018 ◽  
Vol 29 (2) ◽  
pp. 31-36
Author(s):  
Md Dayem Uddin ◽  
Shafayat Habib ◽  
Shakera Sultana ◽  
Khan MMR ◽  
MN Islam ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Neutrophil Recovery ◽  
Nonhematologic Toxicity ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3 ◽  
Carboplatin Auc

Patients and Methods: Topotecan was given as a 30-minute infusion daily for 5 days, with carboplatin given immediately after topotecan on day 5. Treatment was repeated every 21 days. Carboplatin and then topotecan were escalated in sequential cohorts of three to six patients. Four dosage combinations of topotecan days 1 to 5 and carboplatin (day 5) were tested: 0.5 mg/m2/d and carboplatin area under the curve (AUC) of 4, topotecan 0.5 mg/m2/d and carboplatin AUC of 5, topotecan 0.75 mg/m2/d and carboplatin AUC of 5, and topotecan 1.0 mg/m2/d and carboplatin AUC of 5.Results: Grade 3 and 4 neutropenia was common at doses of 0.75 mg/m2/d and above, but dose-limiting hematologic toxicity occurred in only one patient. The most common reason for dose reduction or delay was failure of myelosuppression to resolve by day 21. Nonhematologic toxicity was generally mild. The maximum-tolerated dose as defined in the protocol was not reached, but topotecan dose escalation was stopped at 1.0 mg/m2/d, because delayed neutrophil recovery precluded re-treatment on a 21-day schedule.Conclusion: Hematologic toxicity was common but rarely serious, and the combination of topotecan with carboplatin on this schedule was safe and well tolerated. Giving carboplatin to patients after topotecan on day 5, rather than on day 1, allowed dose escalation beyond the levels reported in other studies. The recommended doses for previously treated patients are topotecan 0.75 mg/m2/d, days 1 to 5, with carboplatin at an area under the curve (AUC) of 5 following topotecan on day 5. The combination of topotecan 1 mg/m2/d, days 1 to 5, followed on day 5 by carboplatin at an AUC of 5, merits further examination in untreated patients.TAJ 2016; 29(2): 31-36

A Dose Escalation Study of RP6530, a Novel Dual PI3K Delta/Gamma Inhibitor, in Patients with Relapsed/Refractory Hematologic Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1495-1495 ◽  
Author(s):  
Carmelo Carlo-Stella ◽  
Richard Delarue ◽  
Prajak J Barde ◽  
Lydia Scarfo ◽  
Thamila Saheb ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Escalation ◽  
Research Funding ◽  
Performance Status ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Hematologic Malignancies ◽  
Prognostic Scores ◽  
Dose Escalation Study ◽  
Human Dose

Abstract Introduction: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell proliferation and survival, cell differentiation, intracellular trafficking and immunity. The delta (δ) and gamma (γ) isoforms of PI3K are often dysregulated in various hematologic malignancies and therefore key targets for the treatment of lymphomas/ leukemia. RP6530 is a novel, highly specific dual PI3K δ/γ inhibitor with nanomolar inhibitory potency that effectively inhibits AKT phosphorylation and induces apoptosis in lymphoma/leukemic cell lines. We herein present results from an ongoing Phase I, first-in-human, dose escalation study of RP6530 (NCT02017613). Methods: The dose escalation will determine the maximum tolerated dose (MTD) of RP6530 using a standard 3+3 design. Patients (pts) with a confirmed diagnosis of hematological malignancy and at least one prior therapy are eligible. Additional eligibility criteria include an ECOG performance status ≤ 2, measurable/evaluable disease, and life expectancy of at least 12 weeks. Primary endpoints are safety and pharmacokinetic (PK) and are supported by secondary endpoints such as pharmacodynamic and efficacy parameters (overall and complete response rates) and correlative biomarkers. RP6530 is given orally twice daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal from study. The study is designed to enroll up to 120 pts in the dose-escalation and expansion phase. Adverse events (AE) are assessed using the CTCAE v4.0/IWCLL guidelines as applicable. Efficacy evaluations are conducted every 8 wks. Results: Twenty six pts were enrolled to date across various dose levels: BID 25mg, 50mg, 100mg, 200mg, 400mg, 600mg and 800mg. Sixteen were males; ECOG score was 0/1/2 in 20/3/3 pts, respectively, with a mean age of 59 yrs (range 20-83). Pts had a median of 5 (range: 1-11) prior treatment regimens, and 19 were refractory to prior treatments. Malignancy categories included HL (9), TCL (4), DLBCL (4), MCL (3), CLL/SLL (2), FL (1), MZL (1), WM (1), and MM (1). Majority of them were considered as "high tumor burden patients" as per different prognostic scores. Sixteen patients were discontinued mainly due to disease progression. RP6530 was well tolerated with no DLT reported to date. Majority of AEs were mild and resolved with/without concomitant medication. None of Grade III/IV AEs or SAEs were deemed related to RP6530. No drug related increase in ALT/AST, colitis, pneumonia, or neutropenia was observed to date. Dose escalation is currently ongoing at 800 mg BID. Single agent activity, manifested by a reduction in tumor size by CT or PET scan, was noticed at ≥ 200 mg BID. The efficacy observations are mostly in indications, that are difficult-to-treat or with minimal therapeutic options. The ORR is 20 % [CR 2 (10 %) + PR 2 (10%)] with disease control rate of 65%. The responders are HL (2), PTCL (1) and DLBCL (1). The CLL/SLL patients, known to be the best responders to selective PI3K inhibitors, were not included in dose-cohorts ≥ 200 mg BID. Clinical response was associated with a significant reduction in pAKT expression. Dose-proportional increase in plasma concentrations were observed upon oral administration of RP6530. Conclusions: To date, RP6530 has been well tolerated in pts with heavily pre-treated relapsed/refractory hematologic malignancies. Reported toxicities were manageable with no DLTs. Single agent activity was evident in difficult-to-treat patients at ≥ 200 mg BID. Enrolment continues at higher dose cohorts. Updated safety, efficacy, PK, and PD data will be presented at the annual meeting. Disclosures Barde: Rhizen Pharmaceuticals SA: Employment. Kumar:Rhizen Pharmaceuticals SA: Employment. Viswanadha:Incozen: Employment. Vakkalanka:Rhizen Pharmaceuticals SA: Employment, Equity Ownership. Ghia:Adaptive: Consultancy; GSK: Research Funding; Acerta Pharma BV: Research Funding; Roche: Consultancy, Research Funding; Pharmacyclics: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau.

A phase I repeated dose escalation study of the Polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumours

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2038-2038 ◽  
Author(s):  
R. Hofheinz ◽  
A. Hochhaus ◽  
S. Al-Batran ◽  
A. Nanci ◽  
V. Reichardt ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Cell Cycle Progression ◽  
High Volume ◽  
Maximum Tolerated Dose ◽  
Solid Tumours ◽  
Moderate Intensity ◽  
Hematologic Toxicity ◽  
Dose Escalation Study ◽  
Bi 2536

2038 Background: BI 2536 is a novel highly potent and selective inhibitor of the serine-threonine kinase polo-like kinase 1 (Plk1), which is a key regulator of cell cycle progression. Objectives of this trial were the assessment of the maximum tolerated dose (MTD), overall safety, pharmacokinetics and efficacy of BI 2536 given intravenously. Methods: Sequential cohorts of 3 to 6 patients (pts) with pretreated advanced or metastatic solid tumours received intravenous infusions of BI 2536 on days 1 and 8 of a 3-week treatment course following a toxicity guided dose escalation design. Further treatment courses were administered to pts in the absence of disease progression and if toxicity after a 3-week treatment course had resolved. Results: A total of 42 pts was treated at doses of 25 mg (n=3), 50 mg (n=3), 100 mg (n=22), 125 mg (n=5), 150 mg (n=6) and 200 mg (n=3). Reversible CTCAE grade ≥ 3 neutropenia in 14/42 pts represented the main drug related toxicity with an incidence of 3/5 in the 125 mg cohort, 4/6 in the 150 mg and 2/2 in the 200 mg dose cohorts. Dose limiting toxicity (DLT) was defined as drug related toxicity prohibiting administration of the day 8 dose of BI 2536 (hematologic: CTCAE ≥ 3 grade, non-hematologic toxicity: CTCAE ≥ 2). No DLT other than d8 neutropenia was observed. The MTD was defined at 100 mg for the given day 1 and 8 schedule. Further related adverse events (AE’s) were of mild to moderate intensity (CTCAE grade ≤ 2). There were no related AEs resulting in study discontinuation. Preliminary PK analysis showed dose proportionality of Cmax and AUC0-∞ with a high clearance (∼ 1500 mL/min) and a high volume of distribution (∼ 2000 L). No accumulation from d1 to d8 occurred. Patients were treated for up to 8 courses without evidence of accumulating toxicity. No objective responses were observed according to RECIST criteria in this heavily pretreated patient population. Conclusions: In summary BI 2536 is a Plk1 inhibitor with a favorable PK and safety profile at the tested dose and schedule. Neutropenia as a mechanism-related toxicity indicates target inhibition in vivo. [Table: see text]

Cladribine and mitoxantrone dose escalation in indolent non-Hodgkin's lymphoma.

1996 ◽  
Vol 14 (7) ◽  
pp. 2139-2144 ◽  
Author(s):  
A Saven ◽  
T Lee ◽  
M Kosty ◽  
L Piro
Keyword(s):  
Dose Escalation ◽  
Overall Response Rate ◽  
Response Rate ◽  
Opportunistic Infections ◽  
Maximum Tolerated Dose ◽  
Combination Regimen ◽  
Indolent Lymphoma ◽  
Dose Escalation Study ◽  
Overall Response ◽  
Major Activity

PURPOSE Since cladribine (2-chlorodeoxyadenosine [2-CdA]) and mitoxantrone both exhibit major activity against indolent lymphoid malignancies and have different mechanisms of action, we performed a dose-escalation study of 2-CdA and mitoxantrone in patients with alkylator-failed indolent lymphoma to determine the maximum-tolerated dose (MTD) of this combination and to make preliminary observations about efficacy. PATIENTS AND METHODS Twenty-three patients were treated every 28 to 35 days, in cohorts of at least three patients, with stepwise dose escalations until dose-limiting toxicities (DLTs) were encountered. The initial dose levels were 2-CdA 0.1 mg/kg/d by continuous infusion for 7 days, mitoxantrone 5 mg/m2 intravenously (i.v.) on day 1, and prednisone 100 mg/d on days 1 to 5. Mitoxantrone was dose-escalated in increments of 2.5 mg/m2 i.v. on day 1. RESULTS The MTD of the combination was 2-CdA 0.1 mg/kg/d for 7 days, mitoxantrone 7.5 mg/m2 i.v. on day 1, and prednisone 100 mg/d on days 1 to 5. Myelosuppression and infection were the DLTs. The recommended phase II doses were 2-CdA 0.075 mg/kg/d for 7 days mitoxantrone 5 mg/m2 i.v. on day 1; prednisone was omitted to decrease the risk of opportunistic infections. The overall response rate was 70%, with 22% complete responses (CRs) and 48% partial responses (PRs). The median duration of CR was 15 months and PR 5 months. CONCLUSION These results demonstrate the feasibility and safety of combining 2-CdA and mitoxantrone in the treatment of indolent lymphoma, and appear to confirm clinically the mechanistic synergism and rationale for this combination regimen. Prednisone exacerbated the risk of opportunistic infection and was omitted. The overall response rate was high, including durable CRs. Further studies of this combination regimen are warranted in untreated and alkylator-failed indolent lymphoma.

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