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<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.

Doxil (D), Vincristine (V), Reduced Frequency Dexamethasone (d) and Revlimid(R) (DVd-R) a Phase I/II Trial in Advanced Relapsed/Refractory Multiple Myeloma (RMM) Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 208-208 ◽  
Author(s):  
Mohamad A. Hussein ◽  
Mary Ann Karam ◽  
Catherine Brand ◽  
Greg L. Pearce ◽  
Janice Reed ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Dose Level ◽  
Response Rate ◽  
Phase 1 ◽  
Performance Status ◽  
High Response Rate ◽  
M Protein ◽  
High Dose ◽  
Grade 3

Abstract DVd in combination with Thalidomide (T) and the appropriate supportive care measures resulted in a high response rate (88%) as well as an improved quality response (50% CR & NCR) similar to what is achieved with high dose therapy. Immunomodulatory drugs (IMiDs) are potent T derivatives. R is 50 to 2000 times more potent than T in stimulating T-cell proliferation triggered via the T-cell receptor, and 50 to 100 times more potent than T in augmenting IL-2 and IFN-a production. A recent phase I trial showed responses of at least 25% reduction in paraprotein in 17 (71%) of 24. We therefore initiated a phase I/II trial to define MTD of R in combination with DVd, then we proceeded to expand the MTD dose level to evaluate the efficacy and safety of the combination in patients with Rmm. SWOG criteria were used to assess response, and NCR was defined as a decrease of the M-Protein by >90%. Refractory patients were defined as those patients progressing on active therapy. R was started a week prior to DVd in cycle 1 to evaluate different coagulation parameters, from there on R was started on day 1 of therapy. The regimen was given as follows: on day 1 D was given at 40 mg/m2 IVPB; V at 2 mg IVP; d at 40 mg PO daily X 4 days; R was started at 5 mg a day for 21 days with one week off. A standard phase 1 dose escalation of R was performed to identify the MTD. 3 pts were enrolled at each dose level, with up to 6 pts assigned to each dose level, depending on DLT. DVd was repeated q 4W, for a minimum of 4 cycles & 2 cycles after best response. Pts were maintained on R +/− prednisone 50 mg QOD. All patients received amoxicillin, acyclovir and aspirin 81mg prophylactically. 25 pts Rmm pts are enrolled with 21 evaluable for toxicity and mature data available for response on 21 pts (refractory: 15 (71%); relapsed: 6 (29%). 17/21 patients were stage 3, median age of 62 ± 9 years, baseline b2 microglobulin level (mean 5.04 ± 2) and serum albumin (mean 3.4 ± 0.7). 14/21 patients failed T containing regimens. The DLT was sepsis/septic shock that occurred at dose level 3 (R 15mg) with two of the patients developing non neutropenic sepsis. The MTD for R was defined at 10mg. Three patients started therapy with a neutrophil count < 500/mL and or platelet counts < 50k/mL; all 3 patients were responders. There was one grade 4 hyper-coagulation event in the form of a PE that has recovered. This event occurred in a refractory patient with renal failure performance status of 3 who achieved CR after 2 cycles. In the expanded cohort there was 2 grade 3 neutropenia & one grade 3 neuropathy requiring dose reductions of R and D in each pt with resolution of the neutropenia and neuropathy. 3/21 (14%) patients achieved CR, 4/21 (19%) NCR. All CR+NCR patients (33%) are refractory patients. An additional 7 pts achieved PR, and 6 SD 5 of whom showing greater than 25% decrease in the m-protein. All patients except for 4 achieved > 25% reduction of the m-protein after one cycle of therapy and 3/4 after 2 cycles. R at 10mg is the MTD in combination with the DVd in RMM. DVd-R is an extremely effective regimen with a SWOG response rate >66%, CR+NCR of 33% in refractory stage 3 patients with minimal toxicity.

Combination of Oxaliplatin Plus Irinotecan in Patients With Gastrointestinal Tumors: Results of Two Independent Phase I Studies With Pharmacokinetics

1999 ◽  
Vol 17 (6) ◽  
pp. 1751-1751 ◽  
Author(s):  
Ernesto Wasserman ◽  
Caroline Cuvier ◽  
François Lokiec ◽  
François Goldwasser ◽  
Salima Kalla ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Two Phase ◽  
Phase I Studies ◽  
Phase Ii Studies ◽  
Minute Period ◽  
Grade 3 ◽  
Febrile Episodes

PURPOSE: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. PATIENTS AND METHODS: Patients with a performance status (PS) of ≤2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m2 for oxaliplatin and 150 to 250 mg/m2 for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m2 plus irinotecan 200 mg/m2 in one study and oxaliplatin 110 mg/m2 plus irinotecan 250 mg/m2 in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2. At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION: This combination is feasible, with activity in 5-FU–resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.

Comparison of Results from a Phase 1/2 Study of Lumiliximab (Anti-CD23) in Combination with FCR for Patients with Relapsed CLL with Published FCR Results.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 32-32 ◽  
Author(s):  
John C. Byrd ◽  
Januario Castro ◽  
Susan O’Brien ◽  
Ian W. Flinn ◽  
Andres Forero-Torres ◽  
...  
Keyword(s):  
Response Rate ◽  
Phase 1 ◽  
Performance Status ◽  
Randomized Study ◽  
Complete Response ◽  
Cancer Center ◽  
Published Data ◽  
Hematologic Toxicity ◽  
Variable Regions ◽  
Overall Response

Abstract Lumiliximab is a PRIMATIZED® anti-CD23 monoclonal antibody with human IgG1 constant regions and macaque variable regions. Preclinical data demonstrated that lumiliximab enhanced both fludarabine- and rituximab- mediated apoptosis in CLL cells. Thus, a Phase 1/2, open-label, dose-escalation, multicenter study (Study 152–30) evaluating lumiliximab + fludarabine, cyclophosphamide, and rituximab (L + FCR) for relapsed CD23+ B-cell CLL was initiated. Treatment has been completed and follow-up is ongoing. Thirty-one patients (pts) received either 375 mg/m2 (n=3) or 500 mg/m2 (n=28) of lumiliximab in combination with a 28-day cycle of FCR for up to 6 cycles. Median age at study entry was 58 yrs. The majority of pts (74%) were Rai Stage I/II. The most common adverse events included nausea (77%), pyrexia (61%), chills (55%), neutropenia (55%), and fatigue (48%). Twenty pts (65%) experienced a Grade 3 or 4 event. An overall response rate of 71% was demonstrated: 48% complete response (CR), 10% partial response (PR), and 13% unconfirmed PR. Currently, baseline cytogenetic data is available for 21 pts who received 500 mg/m2 of lumiliximab. Although preliminary, 1 of the 4 pts with del(17p13.1) responded; of the 6 pts with del(11q22.3), 5 responded with 4 attaining a CR. A comparison with published data from a study of FCR alone in 177 pts with relapsed or refractory CLL conducted at the M.D. Anderson Cancer Center (MDACC) (Wierda W, O’Brien S, Wen S, et al. J Clin Oncol.2005;23:4070–4078) demonstrated that L + FCR has an acceptable safety profile, does not appear to increase the toxicity (including myelosuppression) of the FCR regimen, and compares favorably with the CR rate of the FCR regimen alone, as displayed in Table 1. Most pt characteristics (age, gender, median number of prior therapies, and WHO performance status) were similar between the 2 studies; however, more pts in the MDACC study were Rai Stage III-IV (50% vs 22%) and were rituximab-naïve (88% vs 40%). Furthermore, there were no obvious differences in hematologic toxicity between the 2 studies and the tolerability of L + FCR was similar to that of FCR, with approximately 50% percent of pts completing 6 cycles of treatment in both studies. These data suggest that L + FCR may produce a higher complete response rate than FCR without additional toxicity. Based upon this data, a multicenter, global, randomized study of L + FCR vs. FCR alone is being initiated. Table 1. Comparison of Responses in Study 152–30 and the MDACC Study Study 152–30, L + FCR (N=31), n (%) MDACC, FCR (N =177), n (%) 1CR and PR response criteria were the same in both studies. 2PRu is included in the OR. Overall Response 22 (71%) 130 (73%) Complete Response1 15 (48%) 45 (25%) Partial Response1 3 (10%) 85 (48%) Unconfirmed Partial Response2 4 (13%)

Phase I experience with c-MET inhibitor XL880 administered orally to patients (pts) with solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3526-3526 ◽  
Author(s):  
J. P. Eder ◽  
E. Heath ◽  
L. Appleman ◽  
G. Shapiro ◽  
D. Wang ◽  
...  
Keyword(s):  
Phase I ◽  
Phase 1 ◽  
Performance Status ◽  
Vegf Receptor ◽  
Significant Activity ◽  
Phase Ii Trials ◽  
Ecog Performance Status ◽  
Correlative Studies ◽  
Tumor Biopsies

3526 Background: XL880 is a sub-nM inhibitor of the hepatocyte growth factor receptor (Met) and VEGF receptor family with low in vitro nM inhibition of PDGFRβ, KIT, FLT3, Tie-2 and Ron. Methods: The safety of XL880 was evaluated in two phase 1 studies. XL880 was administered mass-based on a 5 days on / 9 days off schedule (study 1) or as a fixed daily dose (study 2). Inclusion criteria include ECOG performance status = 2, adequate liver, cardiac, and renal function and no brain metastases. Tumor response is assessed every 8 wks by RECIST criteria. Pharmacokinetics, pre and post treatment tumor biopsies and plasma markers of angiogenesis (VEGF, sVEGFR and Ang2) were collected. Results: To date, 51 pts have been dosed in studies 1 & 2. In study 1, dose limiting toxicities (DLT) included reversible Gr3 elevations of lipase, hepatic transaminases and proteinuria. The maximum tolerated dose (MTD) was 3.6 mg/kg. In study 2, the MTD has not been defined. Common adverse events include hypertension and fatigue with loss of concentration. In study 1, 5 of 40 pts had partial responses (2+ -12+ months[m]), 3 pts had minimal responses and 8 pts had stable disease (SD) > 3 m. In study 2, 5 of 8 evaluable pts had SD > 3 m (4 ongoing) and 3 are too early to evaluate. Correlative studies in tumor biopsies show marked inhibition of phospho (p)-met, p-RON, p- ERK, p-AKT and increased apoptosis at less than the MTD. Patients in study 2 pts showed lower XL880 Cmax values with consistent mean concentrations (Css)compared with study 1 MTD pts. Css levels are reached in 15 d. Conclusions: XL880 as daily oral or 5 day on / 9 day off administration is generally well tolerated for > 1 year, although hypertension is nearly universal but manageable. XL880 has demonstrated substantial phase I antitumor activity with both dosing regimens. Correlative studies indicate significant activity against Met and Ron signaling. Enrollment continues on study 2. Phase II trials in gastric cancer and head and neck cancer will begin soon. No significant financial relationships to disclose.

Is a clinical biomarker predictive of outcomes with immune checkpoint inhibitor (ICI) therapy in a phase I patient population.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14136-e14136
Author(s):  
Ulka N. Vaishampayan ◽  
Seongho Kim ◽  
Jaswinder Karwa ◽  
Hirva Mamdani ◽  
Lisa Lange ◽  
...  
Keyword(s):  
Phase I ◽  
Stable Disease ◽  
Clinical Benefit ◽  
Patient Population ◽  
Response Rate ◽  
Cox Regression ◽  
Performance Status ◽  
Retrospective Chart Review ◽  
Predictive Biomarker ◽  
Tumor Type

e14136 Background: NLR is reported to be a prognostic marker in multiple malignancies and has reported potential predictive value with ICI. We evaluated NLR as a predictor of response and time to treatment failure (TTF) in a phase I patient population treated with ICI. Methods: Regulatory approval was obtained. A retrospective chart review of patients treated on phase I trials with ICI based therapy at Karmanos Cancer Institute, was conducted. Data were collected on demographics, performance status, tumor type, response rate, TTF and NLR pre and post therapy. Associations with clinical benefit (response rate and stable disease) and TTF were conducted by univariable logistic and Cox regression analyses. Results: 100 pts; 52 female and 48 male were evaluated. Median age was 62 years (range 22-84 years). 11 were African American (AA) and all patients were pretreated with standard therapy and had progressed prior to enrollment. Median pretherapy NLR was 3.31 (range 0.91-25.5). 26 patients showed clinical benefit with ICI based therapy; 6 partial responses and 20 with stable disease. Univariable Cox analysis for baseline continuous NLR associated with TTF showed a significant relation between NLR and TTF (p = 0.023). Univariable logistic and Cox analyses for dichotomized baseline NLR with optimal cut-off values, resulted in low NLR favoring higher chance of clinical benefit (Odds ratio = 0.169 95% CI 0.028,1.013, p = 0.043) and longer TTF (Hazard ratio = 1.841, 95% CI 1.188,2.854 p = 0.006). Conclusions: Pretherapy NLR was a statistically significant predictor of clinical benefit with ICI therapy in a phase I patient population. NLR is an easily applicable clinical predictive biomarker that may help guide clinical trial choice, especially in a patient population with limited life expectancy.

Azacitidine (AZA) Combined with Idarubicin in Untreated Patients with High Risk MDS – Results of a Phase I/II Study of the Groupe Francophone Des Myelodysplasies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1720-1720 ◽  
Author(s):  
Lionel Ades ◽  
Benoit de Renzis ◽  
Ramzi Jeddi ◽  
Jacques Delaunay ◽  
Thorsten Braun ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Disease Progression ◽  
Stable Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Single Agent ◽  
Overall Response

Abstract Abstract 1720 Background: hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and must be further improved. In addition, if it is able to increase overall survival in MDS, AZA yields only about 30% of marrow response (including CR+PR+ mCR), Idarubicin given at conventional dose (12 mg/m2/d during 3 days) is the anthracycline of choice in the intensive chemotherapy given with cytarabine in patients with high risk MDS and, given as a single agent, induces up to 30% of complete remission (CR) in elderly AML patients. Thus, we designed a phase I/II study evaluating the safety and efficacy of 2 doses of Idarubicin combined with Azacitidine in high risk MDS patients (clinical trial NCT01305135). Methods: For this trial Azacitidine was combined with increasing doses of Idarubicin. Main Inclusion criteria were: (1) IPSS int 2 or high MDS, or CMML with WBC < 13,000/mm3 and marrow blasts > 10% or AML with 20–30% marrow blasts (corresponding to EU label for AZA) (2) Age 3 18 years (3) Performance Status (PS) <=2 (4) no prior treatment except ESAs. Patients received Azacytidine 75 mg/m2/d SC during 7 days every 4 weeks combined on day 8 of each cycle to Idarubicin 5 mg/m2 (administered by 1 hour IV infusion) in the first cohort of 10 patients, escalated to Idarubicin 10 mg/m2 IV in the second cohort of 10 patients after review of toxicity (especially hematological) of the 1st cohort by the independent DSMB r. The primary endpoint of the study was response after 6 cycles according to IWG criteria. Data were analyzed at the reference date of June, 1St 2012. Results: The 20 study patients (from 8 centers) were enrolled between Dec 2010 and Feb 2012, including 7 women and 13 men with a median age of 75 years. At inclusion, WHO classification was RCMD in 1 pt, CMML in 1 pt, RAEB-1 in 6 pts, RAEB-2 in 7 pts, AML in 3 pts and unclassified in 2 pt. Median marrow blasts were 6.5% (0–26) Karyotype (IPSS) was favorable in 7 pts, int in 3 pts and unfav in 8 pts (2 pts had cytogenetic failure). IPSS was high in all patients. PS was 0 in 28% pts, 1 in 50% and 2 in 22%. A total of 92 cycles of treatment had been administrated with a median number of 5 cycles/patient and 10 pts had received 6 or more cycles. 14 patients had terminated the study due to side effects (severe febrile pancytopenia, n=2), disease progression (n=5, after 2–10 cycles), death (disease progression, severe septic shock after Cycle 2, and unrelated coma), stable disease after 6 cycles (n=3), and patient decision (n=1). Overall 7 pt had died. 18 SAEs were reported observed in 9 patients, including 10 episodes of febrile neutropenia, 3 episodes of bleeding and 5 unrelated SAE. Of the 20 patients enrolled in the study, 19 were evaluable for response after 3 cycles, including 10/10 in the First cohort and 9/10 in the second cohort. One patient achieved CR, 2 PR, 1 mCR and 2 additional patients achieved stable disease with HI, leading to an Overall response rate of 6/19 (32%). Two patients were still on study but did not reached cycle 6. Thus, after 6 cycles, 17 patients, only could be evaluated. Among them 9/17 (53%) patients were still on study, 2 pts had died, 3 progressed, 2 had experienced sides effects and had terminated the study and 1 pt had withdrawn consent. Two patients achieved CR (including 1 already in CR at cycle 3), 2 PR and 2 additional patients achieved stable disease with HI leading to an Overall response rate of 6/17 (35%). At the time of the present analysis, none of the responder had relapsed. Conclusion: The phase I/II results presented here show that Idarubicin can be combined to Azacitidine with acceptable toxicity. Whether the azacitidine- Idarubicin combination can improve the outcome of higher risk MDS patients will be evaluated in a phase II randomized trial comparing this combination (and other combinations of azacitidine with other drugs) to azacitdine alone alone. Data of the present phase I/II trial will be updated at the meeting. Disclosures: No relevant conflicts of interest to declare.

Phase I Dose-Escalation Study of Cpi-613, in Combination with Bendamustine, in Relapsed or Refractory T-Cell Non-Hodgkin Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4163-4163 ◽  
Author(s):  
Zanetta S. Lamar ◽  
Scott Isom ◽  
Rakhee Vaidya ◽  
Anne W Beaven ◽  
Zachariah A. McIver
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
T Cell Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Grade 3

Abstract Background:T cell lymphomas account for 10-15% of lymphoid malignancies and display significant heterogeneity. T cell lymphomas have a worse prognosis than most B cell lymphomas. For relapsed or refractory disease, there is not a standard treatment and median progression free and overall survival rates have been reported as 3.7 and 6.5 months, respectively. Therefore, optimal treatment for relapsed/refractory T cell Non-Hodgkin Lymphoma (NHL) is an unmet clinical need. CPI-613 is a lipoate derivative that has shown activity in hematologic malignancies. CPI-613 selectively targets the pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase complex (KGDHC) in tumor cells. CPI-613 leads to the inhibition of the catalytic and regulatory functions of the PDC and the KGDHC causing alterations of mitochondrial enzyme complex activities and altering redox status, leading to apoptosis, necrosis and autophagy of tumor cells. The anti-tumor activity of CPI-613 is evident in various cancer cell lines, xenograft animal tumor models and clinical trials against a diverse group of cancers. Patients tolerate CPI-613 as a single agent at doses up to 3,000 mg/m2, according to Phase 1 trials in patients with solid tumors and hematologic malignancies. Bendamustine has shown single agent activity in the relapsed lymphoma setting with response rates of approximately 50% for T cell NHL. Here, we are conducting a Phase I study in which the primary objective was to evaluate the maximum tolerated dose (MTD) of CPI-613 while administered in combination with Bendamustine. The secondary objective was to determine response rate to treatment. Methods: This study is a phase 1, open label, modified 3+3 dose escalation clinical trial evaluating CPI-613 and Bendamustine combination therapy. CPI-613 was given at escalating doses starting at 2,000mg/m2 over 2 hrs on days 1-4, and on days 8, 11, 15 and 18. Bendamustine was infused at 90 mg/m2 on days 4 and 5 of each treatment cycle. Each treatment cycle was 4 weeks and repeated up to six cycles. Demographics, patient characteristics and dose levels are shown in the table below. There was no intra-patient dose escalation. Results: As of July 27, 2016, eight subjects have received at least one dose of study drug. Eight patients are evaluable for safety and five patients are evaluable for response. The most common grade 3 or higher toxicities were lymphopenia and neutropenia and occurred in 4 subjects. One patient dosed at 2750 mg/m2 had a dose limiting toxicity of grade 3 acute kidney injury and grade 4 lactic acidosis. The protocol was later amended to discontinue dose escalation at doses of 2750 mg/m2 or higher and to expand the 2500mg/m2 cohort. The overall response rate was 80%. Three patients with peripheral T cell lymphoma, NOS, obtained a complete response and 1 patient with mycosis fungoides had a partial response. One patient with T cell acute lymphomoblastic lymphoma had progressive disease. The median time to response is 1.8 months. Enrollment is ongoing and updated trial results will be presented. Conclusions: This first reported study of CPI-613 administration in combination with Bendamustine in subjects with relapsed or refractory T cell lymphoma showed a good safety profile and an excellent overall response rate of 80% with CRs in all three patients with peripheral T cell lymphoma, NOS. Although numbers are small, continued investigation is warranted as these response rates in a poor risk population of patients with relapsed/refractory T cell lymphoma are very exciting. Clinical trial: NCT02168907 Disclosures No relevant conflicts of interest to declare.

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.

scholarly journals Phase I/II trial of dose-reduced capecitabine in elderly patients with advanced colorectal cancer

2017 ◽  
Vol 24 (4) ◽  
pp. 261 ◽  
Author(s):  
M.D. Vincent ◽  
D. Breader ◽  
M.C. Cripps ◽  
D.J. Jonker ◽  
P. Klimo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Advanced Colorectal Cancer ◽  
Response Rate ◽  
Performance Status ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Survival Duration ◽  
Ecog Performance Status ◽  
Pelvic Radiation

BackgroundCombination chemotherapy is associated with improved outcomes in trials of selected fit patients with advanced colorectal cancer (acrc). For older or less-fit patients, combination chemotherapy is associated with greater toxicity and less benefit. Capecitabine monotherapy is a reasonable option for those patients, but the optimal dose remains controversial.MethodsA multicentre phase i/ii trial of reduced-dose capecitabine (2000 mg/m2, days 1–14 every 21 days) was conducted in 221 patients representing one or more of the following subsets: age greater than 65 years (n = 167), Eastern Cooperative Oncology Group (ecog) performance status of 1 or greater (n = 139), elevated lactate dehydrogenase (ldh) (n = 105), or prior pelvic radiation (n = 54). Based on phase i results, patients with prior pelvic radiation received capecitabine 750 mg/m2 twice daily. The goal was to ascertain efficacy in a design that was unlikely to cause high levels of toxicity.Results Median age in the patient cohort was 72 years. A median of 5 and a mean of 8 capecitabine cycles were given (range: 0–50 cycles). Grade 3 or 4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand–foot syndrome, 7.7% diarrhea). The response rate was 13.6%, with a 69.7% disease control rate. Median progression-free survival (pfs) was 5.6 months. Post progression, 56 patients received further capecitabine monotherapy (median of 4 additional cycles). Median overall survival duration for the patients was 14.3 months. Median survival was significantly higher for those who, at baseline, had an ecog performance status of 0 (compared with 1 or more) and normal ldh (compared with elevated ldh).Conclusions Toxicity is less with dose-reduced capecitabine than with historical full-dose capecitabine, with only a small trade-off in efficacy, seen as a lower objective response rate. The improved tolerability could lead to an increased number of cycles of therapy, and pfs appears to be consistently higher at the lower dose. Those observations should, in the absence of a head-to-head clinical trial, be viewed as compelling evidence that 1000 mg/m2, or even 750 mg/m2, twice daily is an appropriate dose in elderly or frail patients with acrc.

Exposure-Response Of Idelalisib, a Novel PI3Kδ Inhibitor, Administered As Monotherapy In The Treatment Of Hematologic Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5054-5054 ◽  
Author(s):  
Feng Jin ◽  
Huafeng Zhou ◽  
Lorna Fang ◽  
Xiaoming Li ◽  
Terry Newcomb ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Response Rate ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Efficacy And Safety ◽  
Plasma Exposure ◽  
Employment Equity ◽  
Exposure Response ◽  
Equity Ownership ◽  
Grade 3

Abstract Background Idelalisib (IDELA) is a potent, competitive PI3Kδ inhibitor currently in Phase 3 clinical development. In numerous Phase 1/2 studies, IDELA alone or in combination with other therapies demonstrated clinical efficacy in patients with various hematologic malignancies (e.g., indolent non-Hodgkin lymphoma [iNHL] and chronic lymphocytic leukemia [CLL]) and overall safety of IDELA has been characterized in these patients. The relationship between IDELA plasma exposures and its inactive circulating metabolite, GS-563117, and clinical efficacy and safety findings were evaluated. Methods IDELA and GS-563117 plasma exposure were generated using population pharmacokinetic (PK) models for IDELA and GS-563117 based on data from several phase 1/2 clinical studies. Efficacy and safety data from 2 clinical studies, a Phase 1 dose ranging study (101-02; 50 mg to 350 mg BID, 150 mg and 300 mg QD) and a Phase 2 study (101-09), were included in the PK/PD analyses. Efficacy endpoints including best overall response rate (BOR), duration of response (DOR), progression free survival (PFS), sum of products of the greatest perpendicular diameters (SPD) of index lesions, and lymph node response rate (LNR) were evaluated against IDELA plasma exposure (AUCtau and Ctau). Safety endpoints evaluated included neutropenia, diarrhea, skin rash, infection, and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation (vs. plasma exposure of IDELA and GS-563117, specifically AUCtau and Cmax). Results Over a wide dose/exposure range in Study 101-02, median SPD response increased with IDELA exposure (Ctau) quartiles, before reaching a plateau at the third quartile (Q3: range ∼280-405 ng/mL), which encompasses the mean IDELA Ctau at 150 mg BID dose (381 [56%] ng/mL). IDELA exposures were less than dose proportional and modestly higher at doses >150 mg BID (eg. Ctau ∼48% higher at 350 mg vs. 150 mg BID). No relationships were observed between the incidence rate (yes/no) of Grade 3 or 4 AST or ALT elevation or the severity (Grade 1 to Grade 4) of elevation over the range of IDELA plasma exposure. Taken together, these data supported the selection of 150 mg BID for further development. No relevant association was observed between IDELA exposure (Ctau: median (Q1, Q3) = 294 (203, 437) ng/mL) vs. any of the efficacy endpoints evaluated in Study 101-09, indicating the absence of exposure-efficacy relationships at 150 mg BID (Table 1). In Study 101-09, no association was observed between IDELA or GS-563117 plasma exposures vs. incidence of neutropenia, diarrhea, rash, infection, or Grade 3 or 4 AST or ALT elevation. Conclusions There were no exposure-response relationships observed for efficacy or safety endpoints at IDELA 150 mg BID, which was selected based on comprehensive exposure-response analyses over a wide dose/exposure range. These data support the use of IDELA 150 mg BID as a monotherapy for treating patients with hematologic malignancies. Disclosures: Jin: Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Fang:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Sciences: Employment, Equity Ownership. Newcomb:Gilead Sciences: Employment, Equity Ownership. Dansey:Gilead: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.

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