Phase I Evaluation of Prolonged-Infusion Gemcitabine With Irinotecan for Relapsed or Refractory Leukemia or Lymphoma

2002 ◽  
Vol 20 (13) ◽  
pp. 2995-3000 ◽  
Author(s):  
Adam J. Bass ◽  
Jon P. Gockerman ◽  
Eve Hammett ◽  
Carlos M. DeCastro ◽  
David J. Adams ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Acute Leukemia ◽  
Phase I ◽  
Phase I Trial ◽  
Overall Response Rate ◽  
Response Rate ◽  
Total Duration ◽  
Hematologic Malignancies ◽  
Prolonged Infusion ◽  
Induction Regimen

PURPOSE: To estimate the maximum-tolerated duration of infusion of gemcitabine at 10 mg/m2/min in combination with irinotecan at 40 mg/m2 daily for 3 days in the treatment of relapsed or refractory acute leukemia or lymphoma. PATIENTS AND METHODS: Patients with leukemia or lymphoma were escalated in separate strata. Stratum I consisted of 11 patients, median age of 47 years (range, 18 to 68 years), with relapsed or refractory leukemia. Stratum II contained nine patients, median age of 48 years (range, 39 to 68 years), who had refractory non-Hodgkin’s lymphoma. Patients received irinotecan at 40 mg/m2 daily for 3 days, beginning just before the first dose of gemcitabine. Gemcitabine was given at 10 mg/m2/min, with the total duration adjusted following a modified continuous reassessment model. RESULTS: Severe myelosuppression and stomatitis/esophagitis were the most serious hematologic and nonhematologic toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours delivered at 10 mg/m2/min (7,200 mg/m2). The overall response rate for one cycle of this therapy in this phase I trial for patients with leukemia was 18% (95% confidence interval, 8% to 45%), and for those with lymphoma, 33% (95% confidence interval, 17% to 66%). CONCLUSION: A prolonged infusion of gemcitabine at 10 mg/m2/min for 12 hours with 3 days of irinotecan at 40 mg/m2/d is a tolerable induction regimen for patients with acute leukemia or lymphoma. Stomatitis/esophagitis should be anticipated; however, this regimen may induce responses in patients with difficult-to-treat hematologic malignancies.

Phase I Evaluation of Prolonged-Infusion Gemcitabine With Mitoxantrone for Relapsed or Refractory Acute Leukemia

2002 ◽  
Vol 20 (3) ◽  
pp. 674-679 ◽  
Author(s):  
David A. Rizzieri ◽  
Adam J. Bass ◽  
Gary L. Rosner ◽  
Jon P. Gockerman ◽  
Carlos M. DeCastro ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Plasma Concentrations ◽  
Fixed Dose ◽  
Prolonged Infusion ◽  
Fixed Dose Rate ◽  
Induction Regimen ◽  
The Mean ◽  
State Concentration

PURPOSE: To ascertain the maximum tolerated duration of infusion of gemcitabine at 10 mg/m2/min in combination with mitoxantrone at 12 mg/m2 daily for 3 days in the treatment of acute leukemia. PATIENTS AND METHODS: Thirty-four patients were enrolled. Stratum I consisted of 26 patients, median age 50 years (range, 25 to 71 years), with relapsed or refractory leukemia. Stratum II contained eight patients, median age 62.5 years (range, 38 to 83 years), who had received fewer than three cycles of myelotoxic therapy for chronic myeloid leukemia or myelodysplasia that had evolved into leukemia. Patients received mitoxantrone at 12 mg/m2 daily for 3 days. After the first mitoxantrone dose, gemcitabine was provided intravenously at 10 mg/m2/min with the duration adjusted by following a continuous reassessment model. RESULTS: Severe myelosuppression, and stomatitis or esophagitis were the most common hematologic and nonhematologic dose-limiting toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours (7,200 mg/m2). The mean steady-state concentration of gemcitabine was 24.72 μmol/L and varied over a fivefold range among patients. Overall response rates in this phase I trial for strata I and II were 42% and 63%, respectively. CONCLUSION: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m2/min for 12 hours with 12 mg/m2/d mitoxantrone for 3 days is a tolerable induction regimen and achieves plasma concentrations sufficient for maximal intracellular activation. Stomatitis or esophagitis should be anticipated; however, this regimen may induce significant responses in patients with difficult-to-treat leukemias.

scholarly journals Phase I Trial of Total Marrow and Lymphoid Irradiation Transplantation Conditioning in Patients with Relapsed/Refractory Acute Leukemia

2017 ◽  
Vol 23 (4) ◽  
pp. 618-624 ◽  
Author(s):  
Anthony Stein ◽  
Joycelynne Palmer ◽  
Ni-Chun Tsai ◽  
Monzr M. Al Malki ◽  
Ibrahim Aldoss ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Phase I ◽  
Phase I Trial ◽  
Transplantation Conditioning

Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia.

1993 ◽  
Vol 11 (9) ◽  
pp. 1652-1660 ◽  
Author(s):  
A F List ◽  
C Spier ◽  
J Greer ◽  
S Wolff ◽  
J Hutter ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Phase I ◽  
Response Rate ◽  
Chronic Phase ◽  
Response To Treatment ◽  
Mdr1 Gene ◽  
Gene Transcript ◽  
Blood Concentrations ◽  
P Glycoprotein ◽  
Dose Dependent

PURPOSE To determine the toxicities and maximum-tolerated dose of cyclosporine (CsA) administered with daunorubicin as a modulator of multidrug resistance (MDR) in acute leukemia, and to evaluate response to treatment and its relationship to mdr1 gene expression. PATIENTS AND METHODS Patients with poor-risk acute myeloid leukemia (AML) received sequential treatment with cytarabine (3 g/m2/d intravenously [i.v.]) days 1 to 5, and daunorubicin (45 mg/m2/d) plus CsA as a 72-hour continuous infusion (CI) days 6 through 8 in a phase I/II trial. A loading dose of CsA administered over 1 to 2 hours preceded the CI. CsA dose escalations ranged from 1.4 to 6 mg/kg (load) and 1.5 to 20 mg/kg/d (CI). Whole-blood concentrations of CsA were monitored by immunoassay; plasma concentration of daunorubicin and daunorubicinol were determined by high-pressure liquid chromatography (HPLC). Specimens were analyzed for P-glycoprotein expression, and results confirmed by a quantitative RNA polymerase chain reaction (PCR) assay for the mdr1 gene transcript. RESULTS Forty-two patients are assessable for toxicity and response. P-glycoprotein was detected in 70% of cases. Dose-dependent CsA toxicities included nausea and vomiting (22%), hypomagnesemia (61%), burning dysesthesias (21%), and prolongation of myelosuppression. Transient hyperbilirubinemia developed in 62% of treatment courses and was CsA-dose-dependent. Reversible azotemia occurred in three patients receiving concurrent treatment with potentially nephrotoxic antibiotics. Steady-state blood concentrations of CsA > or = 1,500 ng/mL were achieved in all patients receiving CI doses > or = 16 mg/kg/d. Mean plasma daunorubicin, but not daunorubicinol, levels were significantly elevated in patients who developed hyperbilirubinemia (P = .017). Twenty-six (62%) patients achieved a complete remission (CR) or restored chronic phase and three patients achieved a partial remission (PR) for an overall response rate of 69% (95% confidence interval, 54% to 84%). The response rate was higher in patients who developed hyperbilirubinemia (P = .001), whereas MDR phenotype did not influence response to treatment. Among five patients with MDR-positive leukemia, cellular mdr1 mRNA decreased (n = 1) or was absent from relapsed specimens (n = 4), while mdr1 RNA remained undetectable at relapse in two patients who were MDR-negative before treatment. CONCLUSION High doses of CsA, which achieve blood concentrations capable of reversing P-glycoprotein-mediated anthracycline resistance in vitro, can be incorporated into induction regimens with acceptable nonhematologic toxicity. Transient hyperbilirubinemia occurs commonly with CsA administration and may alter daunorubicin pharmacokinetics. Recommended doses of CsA for phase II and III trials are a load of 6 mg/kg and CI of 16 mg/kg/d.

Phase I/II study of 72-hour infusional paclitaxel and doxorubicin with granulocyte colony-stimulating factor in patients with metastatic breast cancer.

1996 ◽  
Vol 14 (3) ◽  
pp. 774-782 ◽  
Author(s):  
J S Fisherman ◽  
K H Cowan ◽  
M Noone ◽  
A Denicoff ◽  
S Berg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Overall Response Rate ◽  
Response Rate ◽  
Metastatic Breast ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor ◽  
Doxorubicin Administration

PURPOSE We conducted a phase I/II trial of concurrently administered 72-hour infusional paclitaxel and doxorubicin in combination with granulocyte colony-stimulating factor (G-CSF) in patients with previously untreated metastatic breast cancer and bidimensionally measurable disease. PATIENTS AND METHODS We defined the maximum-tolerated dose (MTD) of concurrent paclitaxel and doxorubicin administration and then studied potential pharmacokinetic interactions between the two drugs. Forty-two patients who had not received prior chemotherapy for metastatic breast cancer received 296 total cycles of paclitaxel and doxorubicin with G-CSF. RESULTS The MTD was determined to be paclitaxel 180 mg/m2 and doxorubicin 60 mg/m2 each by 72-hour infusion with G-CSF. Diarrhea was the dose-limiting toxicity (DLT) of this combination, with three of three patients developing abdominal computed tomographic (CT) scan evidence of typhlitis (cecal thickening) at the dose level above the MTD. All patients developed grade 4 neutropenia (absolute neutrophil count [ANC] < 500 microL), generally less than 5 days in duration. This combination was generally safely administered at dose levels at or below the MTD. The overall response rate was 72% (28 of 39 patients; 95% confidence interval [CI], 55% to 85%), with 8% complete responses (CRs) (three of 39; 95% CI, 2% to 21%) and a median response duration of 9 months. The median overall survival time for all patients is 23 months, with a median follow-up duration of 28 months. Pharmacokinetic studies showed that administration of paclitaxel and doxorubicin together by 72-hour infusion did not affect the steady-state concentrations of either drug. CONCLUSION Concurrent 72-hour infusional paclitaxel and doxorubicin can be administered safely, but is associated with significant toxicity. The overall response rate of this combination in untreated metastatic breast cancer patients is similar to that achieved with other doxorubicin-based combination regimens. The modest complete response rate achieved suggests that this schedule of paclitaxel and doxorubicin administration does not produce significant additive or synergistic cytotoxicity against breast cancer.

scholarly journals Phase I trial of SAR103168, a novel multi-kinase inhibitor, in patients with refractory/relapsed acute leukemia or high-risk myelodysplastic syndrome

2014 ◽  
Vol 56 (2) ◽  
pp. 395-400 ◽  
Author(s):  
Gail J. Roboz ◽  
H. Jean Khoury ◽  
Elias Jabbour ◽  
Wilena Session ◽  
Ellen K. Ritchie ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Leukemia ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Phase I Trial ◽  
Kinase Inhibitor

Phase I trial of Idarubicin (4-demethoxydaunorubicin) in adult acute leukemia

1984 ◽  
Vol 2 (4) ◽  
Author(s):  
M. Hayat ◽  
P. Hurteloup ◽  
C. Parmentier ◽  
P. Carde ◽  
J.O. Pico ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Phase I ◽  
Phase I Trial

Phase I Studies in Hematologic Malignancy: 20-Year Experience from Cancer Therapy Evaluation Program (CTEP) at National Cancer Institute/National Institutes of Health

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-18
Author(s):  
Dai Chihara ◽  
Erich P. Huang ◽  
Shanda R. Finnigan ◽  
Lisa M. Cordes ◽  
Nebojsa Skorupan ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Phase I ◽  
Response Rate ◽  
Hematologic Malignancy ◽  
Phase 1 ◽  
Performance Status ◽  
Hematologic Malignancies ◽  
Phase I Studies ◽  
Grade 5 ◽  
Investigational Agents

Background Phase I study is an essential step of drug development to assess safety, but more recently also to investigate initial insights into potential patient therapeutic response. In the last two decades, treatment of hematologic malignancy has changed dramatically from chemotherapy to targeted agents such as monoclonal antibodies, small molecule inhibitors and immunotherapy. We leveraged a large cohort of phase 1 studies to assess trends in toxicity, response and survival outcomes over time. Methods We reviewed the database of all investigator-initiated phase 1 oncology trials treated patients with hematologic malignancies sponsored by CTEP at the NCI between 2000 and 2019. We report the rates of grade 5 toxicity, response to treatment, and survival outcome following enrollment to the trials. Univariate associations of rates of Grade 5 toxicities possibly, probably, or definitely attributable to treatment and response rate with disease type, year of study activation, or whether each type of treatment was administered were assessed through likelihood ratio tests of a generalized linear mixed model. Results Overall, 3,308 patients were treated in 161 trials. Median age of the patients was 61 (range: 0-96) and 61% were male. Acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) was the most common enrolled malignancy diagnosis (N=1,768) followed by lymphoma (N=921), acute lymphoblastic lymphoma (ALL: N=193) and myeloma (N=153). Forty percent of the trials used an investigational agent as a monotherapy, while 60% of the trials used combination treatment. The most commonly used non-chemotherapy investigational agents were monoclonal antibodies and HDAC inhibitors (28 trials each), followed by DNMT inhibitors (18 trials) and proteasome inhibitors (17 trials). Overall, 468 patients died during trials of which 60 were attributed to the treatment (grade 5 toxicity: 1.81%, 95%CI: 1.36-2.27%). There was a trend of higher grade 5 toxicity in patients with AML/MDS (2.43%) compared to patients with lymphoma (0.98%), ALL (1.55%) or myeloma (0.65%) (p=0.066). Treatment with a PD-1 inhibitor was associated with significantly higher risk of grade 5 toxicities (7.14%, 95%CI: 1.95%-12.3%), compared to patients who did not receive a PD-1 inhibitor (1.65%, 95%CI: 1.21%-2.09%) (odds ratio [OR]: 4.93, 95%CI: 1.54-15.8). The deaths mostly occurred in trials combining a PD-1 inhibitor and a CTLA-4 inhibitor (6 death in 77 pts), although the grade 5 toxicity rate did not significantly differ from PD-1 inhibitor monotherapy (1 death in 21 pts). There was no significant difference in grade 5 toxicity among the time periods when trials were activated (Table. 2000-2005 vs 2006-2012 vs 2013-2019). Baseline characteristics associated with higher risk of grade 5 toxicity were age (OR: 1.02 by 1 year increase in age, 95%CI: 1.01-1.04, p=0.007) and performance status ≥2 at enrollment (OR: 1.56, 95%CI: 1.02-2.39, p=0.039). Response assessment was available in 2,404 patients. Overall response rate (ORR) and CR rate (CRR) from all trials were 25.1% (95%CI: 23.3-26.8%) and 14.7% (95%CI: 13.3-16.2%), respectively. The patients with lymphoma experienced significantly higher ORR (42.8%) compared to patients with AML (18.2%), ALL (13.3%) or myeloma (13.3%). There is a significant increase in both ORR and CRR over time (Table. p&lt;0.001), but the trend of change was different in each disease by investigational agents tested during the period. Monoclonal antibodies, iMIDs, CDK inhibitors and BTK inhibitors were non-chemotherapy agents associated with higher response rate. Overall survival (OS) was available in 2,664 patients. The median OS among all patients after enrollment in phase 1 studies was 277 days (95%CI: 245-305 days). Patients with ALL had significantly shorter median OS (86 days) compared to patients with AML/MDS (255 days), lymphoma (289 days) or myeloma (median not reached). Conclusion There has been a significant improvement of ORR in CTEP sponsored phase I studies in the last 20 years. Grade 5 toxicity rate remained low, but higher age and poor performance status were associated with higher risk. Participation in phase I studies should be encouraged in patients with hematologic malignancies. Table Disclosures No relevant conflicts of interest to declare.

A Phase I/II Study of Bortezomib and Low Dose Intravenous Melphalan (BM) for Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2555-2555 ◽  
Author(s):  
Rakesh Popat ◽  
Heather E. Oakervee ◽  
Nicola Foot ◽  
Samir Agrawal ◽  
Patricia Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progressive Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Median Number ◽  
Overall Response ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background: Bortezomib as a single agent has known efficacy in the treatment of relapsed multiple myeloma. The overall response rate (CR+PR+MR) was 35% in the SUMMIT study and 46% in the APEX study. In-vitro studies including our own have demonstrated potent synergy with other chemotherapeutic agents such as melphalan. It therefore follows that responses to bortezomib may be further improved by the combination of such drugs. Aims: The primary objectives of this Phase I/II study was to assess the safety, tolerability and response rates in patients with relapsed multiple myeloma; secondary objectives being time to progression (TTP) and overall surival (OS). Methods: This was a multi-centre, non-randomised trial for patients with relapsed myeloma. Patients received bortezomib 1.3mg/m2 on days 1,4,8 and 11 of each 28 day cycle with melphalan on day 2 at increasing dose levels. This was initially at 10mg/m2, but due to cytopenias subsequently at 2.5 and 5mg/m2 (levels 1a, 1 and 2) and we plan to escalate to 7.5mg/m2. Up to 8 cycles were given with dexamethasone added for stable or progressive disease after 4 or 2 cycles respectively. Responses were determined by EBMT criteria. Results: To date, 18 patients have been enrolled (12 male 6 female; median age 60 [range 44–73]; median number of prior therapies 3 [range 1–5] of which 17 have had at least one autologous stem cell procedure with high dose melphalan; 10 prior thalidomide and 2 prior bortezomib). 12 patients received melphalan at 10mg/m2 but due to unacceptable delays predominantly due to thrombocytopaenia, subsequent treatment levels commenced at 2.5mg/m2. The median number of cycles completed thus far is 4 (range 0–8) and of the 16 evaluable, the overall response rate (CR+PR+MR) across all treatment levels was 50% rising to 75% following the addition of dexamethasone as per protocol. At level 1a (melphalan 10mg/m2 ,N=12, median number of cycles completed =5) the best responses (with dexamethasone as indicated) were: 1CR, 1 VGPR, 5 PR, 2 MR; at level 1 (melphalan 2.5mg/m2, N=4) 1 PR, 2 MR (after 2 cycles only). The median time to any response was 1 cycle (range 1–3 ). Three patients have progressive disease, but the median TTP and OS have not yet been reached (median follow-up 3 months). Non-haematological toxicities have been modest with 7 SAEs reported of which only 1 was possibly drug related (myocardial infarction), and 4 episodes of Grade 3 neuropathy (2 resulting in study withdrawal). The commonest grade 3–4 haematological toxicity was thrombocytopaenia (N=10) complicated by bleeding in one patient, followed by neutropenia (N=6). Summary: The combination of bortezomib and intravenous melphalan can be given safely to patients with relapsed multiple myeloma and dose escalation is ongoing. Myelosupression was the commonest grade 3–4 adverse event. A response rate of 50% was seen, which was further improved to 75% with the addition of dexamethasone. This combination may therefore result in higher responses than single agent bortezomib in heavily pretreated patients.

A Phase I/II Trial of Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3542-3542 ◽  
Author(s):  
Rakesh Popat ◽  
Catherine Williams ◽  
Mark Cook ◽  
Charles Craddock ◽  
Supratik Basu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Median Time ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Chemotherapeutic Agents ◽  
Time To Progression ◽  
Overall Response ◽  
Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (MR+PR+CR) of 46% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were classified by EBMT criteria. Results: To date 39 patients have been enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. 36 have now completed at least 1 cycle and are therefore evaluable for response. The overall response rate (CR+PR+MR) across all treatment levels was 75% rising to 81% (CR 11%; nCR 3%; VGPR 8%; PR 39%; MR 19%) with the addition of dexamethasone in 13 cases for suboptimal response. Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression is 10.1 months and the median overall survival has not yet been reached at a median follow-up of 7.4 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 13 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma where a response rate of 81% is seen with 14% achieving nCR/CR. The toxicity profile associated is predictable, manageable and predominantly haematological. Recruitment is ongoing to a total of 53 patients.

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