Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase I safety and efficacy analyses.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4073-4073 ◽  
Author(s):  
Robin Kate Kelley ◽  
Ghassan K. Abou-Alfa ◽  
Johanna C. Bendell ◽  
Tae-You Kim ◽  
Mitesh J. Borad ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Progressive Disease ◽  
Hospice Care ◽  
Randomized Study ◽  
Immune Checkpoints ◽  
Clinical Activity ◽  
Open Label ◽  
Study Results ◽  
Grade 3

4073 Background: Durvalumab and tremelimumab, investigational monoclonal antibodies against PD-L1 and CTLA-4 immune checkpoints, respectively, have shown efficacy in monotherapy and offer promise in combination for patients (pts) with HCC. This is a phase I/II, open-label, randomized study of durvalumab combined with tremelimumab in unresectable HCC. Methods: Phase I part of this study is a safety run-in cohort treated at the recommended phase II doses of the durvalumab/tremelimumab combination (20 and 1 mg/kg IV Q4W respectively for 4 doses followed by 20 mg/kg Q4W durvalumab alone) in pts with unresectable HCC with or without concomitant HBV or HCV infection who progress on, are intolerant to, or have refused sorafenib therapy. Secondary objectives include evaluation of antitumor activity. Here we present results of a preplanned analysis from the completed phase I part of the study. Results: As of 10 January 2017, 40 pts have been enrolled (11 HBV+, 9 HCV+, 20 uninfected). 30% had no prior systemic therapy; 93% were Child Pugh Class A. 24 (60%) had ≥1 treatment-related AE; 20% had ≥1 grade ≥3 related AE. Most common (≥15%) treatment-related AEs: fatigue (20%), increased ALT (18%), pruritus (18%), and increased AST (15%). Most common grade ≥3 related AE was asymptomatic increased AST (10%). 24 pts have discontinued treatment: 3 due to treatment-related AEs (grade 3 pneumonitis, grade 3 colitis/diarrhea, asymptomatic grade 4 elevated AST and ALT), 16 due to progressive disease, 4 due to death unrelated to treatment (cardiac arrest, variceal bleed, progressive disease, probable HCC rupture), and 1 other (pt entered hospice care). 40 pts were evaluable for response at ≥16 weeks follow-up. Conclusions: No unexpected safety signals with durvalumab and tremelimumab were seen in this unresectable HCC population. Clinical activity observed predominantly in uninfected pts though interpretation limited by small subsets. Enrollment to the phase II portion of the study is ongoing. Clinical trial information: NCT02519348. [Table: see text]

A Phase I Study of Vorinostat in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3705-3705 ◽  
Author(s):  
David Siegel ◽  
Donna Weber ◽  
Constantine S. Mitsiades ◽  
Syed Rizvi ◽  
Jose Garcia-Vargas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progressive Disease ◽  
Therapeutic Potential ◽  
Hematologic Malignancy ◽  
Randomized Study ◽  
Single Agent ◽  
Clinical Activity ◽  
Open Label ◽  
Tumor Types

Abstract Introduction: Multiple myeloma (MM) is the second most common hematologic malignancy after non-Hodgkin’s lymphoma and despite recent advances in therapy, including the introduction of thalidomide, bortezomib, and lenalidomide, remains incurable. Vorinostat is an inhibitor of Class I and II histone deacetylases, which play key roles in the regulation of both transcriptional and post-transcriptional activity in a variety of tumor types, including MM. This histone deacetylase inhibitor has demonstrated anti-proliferative activity as monotherapy and synergistically with other agents in a variety of tumor types, including MM, where it was well tolerated in Phase I trials. Lenalidomide is a potent structural analog of thalidomide and demonstrates clinical efficacy in the treatment of MM as a single agent and to a larger degree, in combination with dexamethasone. Preclinical data suggest that the addition of vorinostat to lenalidomide and dexamethasone has at least additive, and possibly synergistic, therapeutic potential, with the anti-tumor mechanisms of vorinostat and dexamethasone being distinct from the immunomodulatory effects of lenalidomide. This Phase I, multicenter, open-label, non-randomized study assessed the safety and tolerability of vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory MM. Methods: The primary objective was to determine the maximum tolerated dose (MTD). Secondary and exploratory objectives included: assessment of safety and tolerability; determination of clinical activity of the combination, and evaluation of in vivo molecular and biologic effects of the combination in patients with MM through analysis of gene expression. Patients aged ≥18 years with an established diagnosis of relapsed or refractory MM were enrolled sequentially into 1 of 5 dosing levels (table). Patients received vorinostat daily, administered orally for 14 days with 7 days on (Days 1–7 and 15–21), combined with oral lenalidomide daily for 21 days, and oral dexamethasone 40 mg/day (Days 1, 8, 15, and 22; cycles were repeated every 28 days); use of concomitant prophylactic acetylsalicylic acid was recommended. Dose-limiting toxicities (DLTs) were assessed in the first treatment cycle. Barring DLT, dose escalation continued until the MTD was established. Response, safety, and tolerability were evaluated. Adverse events (AEs) were recorded throughout the study. Dosing Regimen Dose Level Vorinostat Dose (mg q.d.) 7 days on 7 days off (Days 1–7 and Days 15–21) in each 28-day cycle Lenalidomide Dose (mg q.d.) × 21 days (Day 1 through Day 21) in each 28-day cycle Dexamethasone Dose (mg q.d.) On Days 1, 8, 15, and 22 in each 28-day cycle 1 300 10 40 2 400 10 40 3 400 15 40 4 400 20 40 5 400 25 40 Results: Enrolment is ongoing and tolerability of treatment has been good so far. Of 7 patients assessed to date, 6 patients (86%) have reported ≥1 AE, and 3 patients’ (43%) AEs were considered drug-related. The most frequently reported AE was anemia (n=4, 57%). Serious AEs were reported by 2 patients (29%), none of which were considered drugrelated. No patients have discontinued due to AEs or SAEs, and no DLT has been observed to date. Of 6 evaluable patients, the best responses were: partial response in 1 patient, minimal response in 1 patient and stable disease in 2 patients and progressive disease in 2 patients. Currently, 4 patients remain on treatment and 3 patients have discontinued treatment due to progressive disease. Conclusion: Vorinostat with lenalidomide and dexamethasone represents a novel combination therapy for the treatment of relapsed or relapsed, refractory MM. Preliminary results suggest that the combination is well tolerated to date, is active and has the convenience of oral administration.

X-TRAP: Phase I/II study of capecitabine (X) plus ziv-aflibercept (TRAP) in metastatic colorectal cancer (mCRC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 687-687 ◽  
Author(s):  
John H. Strickler ◽  
Fatima A. Rangwala ◽  
Christel Rushing ◽  
Donna Niedzwiecki ◽  
Ivy Altomare ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Oral Mucositis ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Clinical Activity ◽  
Combination Methods ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Expansion Cohort

687 Background: Patients (pts) with chemotherapy refractory mCRC have a poor prognosis, with a median survival of approximately 6 months (mos). Ziv-aflibercept is FDA-approved in combination with FOLFIRI for the 2nd line treatment of mCRC, but its tolerability and activity in pts with chemotherapy refractory disease is unknown. We designed a phase I/II study of X+TRAP to define the recommended phase II dose (RPTD), and assess the safety, tolerability, and clinical activity for the combination. Methods: Eligible pts with refractory, advanced solid tumors were enrolled in a 3+3 dose escalation cohort (ESC) to identify the RPTD. Cycle length was 21 days. Radiographic assessment occurred every 3 cycles. X was administered po bid on days 1-14. The dose of X was 850 mg/m2 bid in ESC cohort 1 and 1,000 mg/m2 bid in ESC cohort 2. TRAP was administered on day 1 of each cycle (6 mg/kg IV). Pts with mCRC that had progressed on all standard therapies were then enrolled in a single-arm, phase II expansion cohort (EXP) and treated at the RPTD. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Results: As of 6/19/2015, 55 pts were evaluable for toxicity (13 ESC; 42 EXP) and 47 pts were evaluable efficacy (12 ESC; 35 EXP). In the phase I ESC cohorts, 3 DLTs occurred (1/6 cohort 1; 2/6 cohort 2): GI perforation (1), oral mucositis (1), and fatigue (1). The RPTD was X (850 mg/m2 po bid, days 1-14) and TRAP (6 mg/kg IV, day 1). In the ESC and EXP cohorts, there were no treatment related grade 4/5 adverse events (AEs). The most frequently reported treatment related AEs (grades 2+3; grade 3) were palmar-plantar erythrodysesthesia (36%; 5%), hypertension (29%; 20%), and oral mucositis (18%; 4%). Median follow up in the phase II EXP cohort was 9.3 mos (95% C.I., 6.5–11.1). Median PFS was 4.1 mos (95% C.I., 2.3-4.8). Response assessment in 35 pts (n; %): partial response (PR) (2; 6%); stable disease (SD) (12; 34%); SD > 6 mos (2; 6%). Median OS was 9.3 mos (95% C.I., 6.2–n/a). Conclusions: The combination of X+TRAP demonstrated an acceptable safety profile, with encouraging clinical activity at the RPTD. Recruitment for the phase II EXP cohort is now complete. Clinical trial information: NCT01661972.

Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4503-4503 ◽  
Author(s):  
David C. Smith ◽  
Thomas Gajewski ◽  
Omid Hamid ◽  
Jeffrey S. Wasser ◽  
Anthony J. Olszanski ◽  
...  
Keyword(s):  
Phase I ◽  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Advanced Disease ◽  
Alternative Therapy ◽  
Phase Iii ◽  
Open Label ◽  
Advanced Urothelial Carcinoma ◽  
Grade 3 ◽  
Line Of Therapy

4503 Background: Pembrolizumab (P), a PD-1 inhibitor, is active and well tolerated in platinum-treated, advanced urothelial carcinoma (UC). Epacadostat (E) potently and selectively inhibits indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that suppresses T-cell–mediated immune surveillance. IDO1 overexpression is associated with tumor progression and shortened patient (pt) survival. ECHO-202/KEYNOTE-037 is an open-label, phase I/II study of E + P in pts with advanced tumors. We report phase I/II efficacy and safety outcomes for the UC cohort at an October 29, 2016 data cutoff. Methods: Adult pts with advanced UC, prior platinum therapy (adjuvant or advanced disease setting) or alternative therapy (if platinum was not appropriate), and no prior checkpoint inhibitor therapy were eligible to participate. In phase I, pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for phase II. Response was assessed in RECIST 1.1–evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: A total of 40 pts (phase I, n = 5; phase II, n = 35) were evaluated. Median age was 67 years, 75% were men, 88% were white, 100% had prior platinum therapy, and 75% had 0–1 prior line of therapy for advanced disease. Preliminary ORR (CR+PR) and DCR (CR+PR+SD) for all efficacy-evaluable pts were 35% (13/37; all PR) and 57% (21/37; 13 PR, 8 SD), respectively; for pts with 0–1 prior line of therapy for advanced disease, ORR and DCR were 37% (10/27) and 63% (17/27). At data cutoff, 12/13 responses were ongoing (range, 1+ to 652+ days). PFS and biomarker analyses are ongoing. The most common TRAEs (≥10% of 40 pts) were fatigue (28%), rash (18%), and increased amylase (10%; asymptomatic). Grade ≥3 TRAEs occurred in 20% of pts (rash was the only grade ≥3 TRAE to occur in > 1 pt [n = 3]). Three pts discontinued due to TRAEs (grade 3 rash [n = 1]; grade 3 COPD exacerbation [n = 1], grade 2 diarrhea [n = 1]). Conclusions: E + P was generally well tolerated and associated with increased response compared with previously reported PD-1 inhibitor monotherapy in pts with advanced UC. A phase III UC study is planned. Clinical trial information: NCT02178722.

scholarly journals Daily Oral Everolimus Activity in Patients With Metastatic Pancreatic Neuroendocrine Tumors After Failure of Cytotoxic Chemotherapy: A Phase II Trial

2010 ◽  
Vol 28 (1) ◽  
pp. 69-76 ◽  
Author(s):  
James C. Yao ◽  
Catherine Lombard-Bohas ◽  
Eric Baudin ◽  
Larry K. Kvols ◽  
Philippe Rougier ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase Ii ◽  
Progressive Disease ◽  
Objective Response ◽  
Neuron Specific Enolase ◽  
Progression Free Survival ◽  
Pancreatic Neuroendocrine Tumor ◽  
Clinical Activity ◽  
Open Label ◽  
Octreotide Lar

PurposeNo established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs.Patients and MethodsThis open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed.ResultsBy central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus.ConclusionDaily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.

Natural history of diarrhea associated with the anti-CTLA4 monoclonal antibody CP-675,206

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3038-3038 ◽  
Author(s):  
S. Antonia ◽  
J. Sosman ◽  
J. M. Kirkwood ◽  
B. Redman ◽  
T. F. Gajewski ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Range ◽  
Objective Response ◽  
Stage Iv ◽  
Open Label ◽  
Similar Frequency ◽  
Severe Diarrhea ◽  
Grade 3 ◽  
Stage Iv Melanoma

3038 Background: Diarrhea resulting from immune activation has been associated with CTLA4 blockade. For example, in patients (pts) with stage IV melanoma receiving ipilimumab (MDX-010), a number of pts developed grade 3/4 autoimmune enterocolitis and severe diarrhea (Attia et al, 2005). In a single-dose phase I trial of CP-675,206 at doses up to 15 mg/kg in pts with solid tumors (n = 39), 9 instances of diarrhea were reported including 3 grade 3 events (Ribas et al, 2005). The incidence and severity of diarrhea was assessed in pts receiving CP- 675,206 in a large phase I/II study. Methods: An open-label phase I/II trial of CP-675,206 was conducted in pts with stage III (unresectable) or stage IV melanoma and an ECOG PS = 1. Diarrhea was assessed in pts treated at the phase II doses: 10 mg/kg monthly (Q1M) in phase I (n = 22), or 10 mg/kg Q1M (n = 44) or 15 mg/kg every 3 months (Q3M, n = 45) in phase II. Results: Medians of 3.5 doses (range, 1 to 18) at 10 mg/kg Q1M in phase I, 3 doses (range, 1 to 26) at 10 mg/kg Q1M in phase II, and 1 dose (range, 1 to 9) at 15 mg/kg Q3M were administered with 100% dose compliance. Treatment-related diarrhea was reported by 43 (39%) of 111 pts, and grade 3 diarrhea occurred in 14 (13%) pts. One patient had grade 4 colitis resulting in a colectomy. Diarrhea (all grades) occurred with similar frequency in each dose group; however, grade 3 treatment-related diarrhea occurred in 8% of pts treated with 15 mg/kg Q3M compared with 18% of pts treated with 10 mg/kg Q1M in phase I and 14% of pts treated with 10 mg/kg Q1M in phase II. Among 9 pts with an objective response, 8 experienced diarrhea (3 of which were grade 3). The majority of cases (65%) were mild to moderate in severity with a median time to onset of 51 days (range, 1 to 583 days) and resolution of 8 days (range, 1 to 182 days). More than half of pts who reported serious events of diarrhea were treated with steroids. Conclusions: Diarrhea associated with CP-675,206 was primarily mild to moderate in severity, transient, and manageable. In addition, 15 mg/kg Q3M may be better tolerated than 10 mg/kg Q1M. Ongoing clinical trials in pts with advanced melanoma will provide further information about the incidence, severity, and optimal management of diarrhea associated with CP-675,206. No significant financial relationships to disclose.

Phase I study of obatoclax mesylate (GX15–070MS), a bcl-2 antagonist, plus topotecan in relapsed small cell lung carcinoma and other solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3504-3504
Author(s):  
A. B. Brown ◽  
C. Rudin ◽  
N. Rizvi ◽  
W. Travis ◽  
N. Takebe ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Dose Escalation Study ◽  
Cell Lung Carcinoma ◽  
Grade 3

3504 Background: Bcl-2 is a rational target in SCLC since it is overexpressed in 60%-90% of tumors and may play a role in resistance of SCLC to chemotherapy. Obatoclax is a small molecule BH3 mimetic that blocks bcl-2 binding to proapoptotic family members. Obatoclax has growth inhibitory effects in several solid tumor cell lines and xenografts, with at least additive effects in combination with topotecan. The primary objective of this study was to evaluate the safety profile and maximum tolerated dose (MTD) of obatoclax plus topotecan in patients with relapsed SCLC and other solid tumors. Methods: We conducted a phase I dose escalation study using a standard “3+3” design. Obatoclax was administered at 14 or 20 mg/m2 over 3 hours on day 1 every 21 days. A subsequent cohort received obatoclax 14mg/m2 on days 1 and 3. Topotecan was given at 1.25 mg/m2 days 1–5. All patients received pegfilgrastim on day 8. Eligible patients were adults with solid tumors appropriate for treatment with topotecan. Patients with neurologically stable, treated brain mets were eligible. Results: 14 patients have been treated including 8 SCLC, 3 extrapulmonary small cell, 1 carcinoid, 1 Merkel cell and 1 melanoma previously treated with 1 or 2 lines of chemotherapy. Nearly all patients experienced neurologic toxicities during the obatoclax infusion which included ataxia, dysarthria, somnolence and/or mood alteration; these typically resolved 1–2 hours after completion of the infusion. The MTD of obatoclax was 20 mg/m2 on day 1 with Dose Limiting Toxicities (DLT) including grade 3 neurotoxicity (2 pts) and febrile neutropenia. Hematologic toxicity included grade 3/4 anemia (6 pts), thrombocytopenia (5 pts) and neutropenia (5 pts). Other toxicities included mild nausea/vomiting, fatigue, pruritus, and constipation. Clinical activity was seen in patients with SCLC including 1 PR and 4 SD out of 7 evaluable. The median TTP for these SCLC patients was 11 weeks. Conclusions: The recommended phase II dose is obatoclax 14 mg/m2 on days 1 and 3 with topotecan 1.25 mg/m2 on days 1–5 in 21 day cycles. A phase II study in second-line SCLC is open. Supported by NCI U01-CA69856. No significant financial relationships to disclose.

Phase I/randomized phase II trial of either dasatinib or placebo combined with standard chemoradiotherapy for newly diagnosed glioblastoma multiforme (GBM): Final results of phase I study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2032-2032 ◽  
Author(s):  
Nadia N. Laack ◽  
Evanthia Galanis ◽  
Clinton Leinweber ◽  
Jan C. Buckner ◽  
Caterina Giannini ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Progressive Disease ◽  
Phase Ii Trial ◽  
Newly Diagnosed ◽  
Entire Study ◽  
Randomized Phase Ii ◽  
Level 1 ◽  
Grade 3

2032 Background: Dasatinib is a potent oral ATP competitive multi-targeted kinase inhibitor of multiple members of the Src kinase family, known to be involved in gliomagenesis and invasion. N0877 is a phase I/randomized phase II trial evaluating the combination of dasatinib, radiation (RT) and temozolomide (TMZ) in newly diagnosed GBM. The phase I portion has been completed and is the focus of this report. Methods: A cohorts-of-3 design was used to assess the safety of dasatinib in combination with RT and concomitant TMZ, and establish the phase II dose of the combination. Dasatinib was given orally for 42 days, beginning with the first day of RT (total dose 60 Gy) and first dose of TMZ (75 mg/m2/d). A 24 - 42 day rest (cycle 2) followed the RT/TMZ/dasatinib. Patients (pts) were observed for DLT to the end of cycle 2. Patients then received 6 cycles (28 day cycles) of dasatinib (once daily) and TMZ (days 1-5). At the completion of 6 cycles of TMZ + dasatinib, pts stay on dasatinib only (28 day cycles) until progressive disease. Results: Phase I component is complete with 13 patients (3 at dose level 0, 3 at dose level 0-A, 7 at dose level 1). One patient in dose level 1 had to be replaced due to the development of unrelated medical issues. One DLT (grade 4 pancytopenia) was observed in 1 patient at dose level 0 (50mg bid) and one DLT (grade 3 rash) was observed in 1 patient at dose level 1 (150mg qd). MTD of dasatinib was determined to be 150mg daily. Most common adverse events throughout the entire study period were hematologic with the most common toxicity being lymphopenia (grade 3 in 69% of patients, grade 4 in 8%). Other toxicities attributed to treatment and occurring in > 10% of patients included anemia (31%), neutropenia (15%), and fatigue(15%). Best response was stable disease in 10 patients, progressive disease in 1 patient, and not evaluable in 2. Conclusions: MTD for dasatinib in combination with TMZ and RT in newly diagnosed GBM patients is 150mg daily. Toxicity was primarily hematologic with minimal non-hematologic events. This dose is currently being used in the ongoing placebo-controlled, randomized phase II trial.

Phase I/II study of weekly topotecan and gefitinib in patients with platinum-resistant ovarian, peritoneal, or fallopian tube cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6059-6059
Author(s):  
Anca Chelariu- Raicu ◽  
Charles F. Levenback ◽  
Brian M. Slomovitz ◽  
Diane C. Bodurka ◽  
David Marc Gershenson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Phase I ◽  
Dose Level ◽  
Fallopian Tube ◽  
Phase Ii ◽  
Response To Therapy ◽  
Clinical Activity ◽  
Study Results ◽  
Level 3

6059 Background: The epidermal growth factor receptor (EGFR) is expressed in many types of cancer. Fifty to 70% of epithelial ovarian can overexpress EGFR, and its expression has been correlated with poor prognosis features in many cases. While these tumors are chemosensitive to platinum-based therapy, chemoresistance often develops. We conducted a phase I/II trial to examine the efficacy, safety, and toxicity of gefitinib, a tyrosine kinase inhibitor, combined with topotecan in women with recurrent ovarian cancer with EGFR receptor positivity (1+ or greater). Methods: Patients with measurable, recurrent or persistent cancer after treatment with a platinum and paclitaxel-containing regimen were eligible for this study (n = 19). We first used “run-in” dose escalation, in which a conventional 3+3 algorithm was used. Initial treatment was gefitinib 250 mg oral dose daily and topotecan at a dose of 2.0 mg/m2 on days 1, 8, and 15, with cycles repeated every 28 days. Dose escalations were planned for topotecan (Dose Levels 1–3: 2, 3, 4 mg/m2) until the MTD was reached. Next, an additional 10 patients with refractory or progressive ovarian cancer were enrolled in the phase II study. Results: 19 patients received a total of 61 cycles. Median age was 60 years. Histological types of treated patients included 73% serous (n = 14), 12.5% mixed (n = 2), 12.5% transitional (n = 2) and 6.3% clear cell (n = 1). There were 3 patients treated at dose level 1, 3 patients at dose level 2, and 3 patients treated at dose level 3. The maximum tolerated dose was topotecan 4.0mg/m2 IV days 1, 8 and 15, and gefitinib 250mg p.o. QD x28 days. Therefore, dose level 3 was used for the Phase II portion of the trial. Of the 19 patients included in the phase I/II, 3 patients were inevaluable for response to therapy due to toxicity, missed therapy or decline in performance status. Of the 16 patients, 81% patients (n = 13) had progressive disease, 12.5% stable disease (n = 2), and 6% partial response (n = 1). We assessed all 19 patients for adverse events; 60% had treatment-related grade 3 events, primarily blood disorders such as anemia (n = 3, 16%), neutrophil count decrease (n = 4, 21%). Conclusions: This prospective phase I/II clinical trial failed to show sufficient clinical activity of topotecan in combination with gefitinib in patients with EGFR-positive recurrent ovarian, fallopian tube, or peritoneal cancers. The drug combination was relatively well-tolerated in this cohort. As such, the study did not proceed to the next accrual goal secondary to the lack of response. Clinical trial information: NCT00317772.

A phase I/II study to evaluate the safety and efficacy of a novel long-acting interleukin-7, NT-I7, for patients with newly diagnosed high-grade gliomas after chemoradiotherapy: The interim result of the phase I data.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2040-2040
Author(s):  
Jian Li Campian ◽  
Jingqin Luo ◽  
Chai Avvaru ◽  
Ruth Katumba ◽  
Albert H Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Randomized Study ◽  
Newly Diagnosed ◽  
Interleukin 7 ◽  
Cytokine Analysis ◽  
Grade 3 ◽  
Long Acting ◽  
Dose Dependent ◽  
Immune Profiling

2040 Background: High-grade gliomas (HGG) patients can develop prolonged lymphopenia after standard radiation therapy (RT) and temozolomide (TMZ), which has been shown to correlate with worse survival. Interleukin-7 (IL-7) level, a cytokine that stimulates T-cell homeostasis and proliferation, is disproportionally low in HGG patients with lymphopenia. NT-I7 (efineptakin alfa) is the first-in-class long-acting recombinant human IL-7 that supports proliferation and survival of CD4+ and CD8+ T-cells in humans and mice. Our previous study demonstrated that NT-I7 could correct lymphopenia and improve the survival of orthotopic murine glioma models. The current study aims to examine the safety of administering NT-17 after chemoradiotherapy to HGG patients and its effect on systemic absolute lymphocyte count (ALC). Methods: All patients with newly diagnosed HGG who have completed concurrent RT/TMZ were considered eligible, regardless of ALC. NT-I7 was initially administered intramuscularly within 1 week after completion of RT/TMZ and then every 12 weeks for up to 4 doses. Patients also received adjuvant TMZ 4 weeks after RT/TMZ. The phase I study tested 6 dose levels of NT-I7, including 60, 120, 240, 540, 720, and 960 mcg/kg, adopting an accelerated phase for the first two doses followed by the standard 3+3 design. The primary endpoint was the safety of NT-I7 in HGG. The Phase II study is a double-blinded randomized study with 10 patients per arm to evaluate the effect of NT-I7 on ALC compared to placebo controls. Blood samples at baseline and during the NT-I7 administrations will be collected for immune profiling by CyTOF, single-cell RNA-sequencing, and cytokine analysis. Results: Phase I was completed with 19 patients (2 anaplastic oligodendrogliomas and 17 glioblastomas), with a median age of 58 years (range: 25-78). Median baseline ALC was 1000 cells/mm3 before NT-I7 administration, and the median baseline dexamethasone use was 0 mg/day (range 0-12). The median number of NT-I7 doses given was 2 (range: 2-4). Treatment-related adverse events (TRAEs) were dose-dependent. The most common TRAEs were grade 1/2 injection site reactions (50%), flu-like symptoms (26%), rash (21%), and fatigue (21%). Two patients had dose-limiting toxicities at 960 mcg/kg (a grade 3 elevated alanine aminotransferase and a grade 3 muscle pain). ALC was increased in a dose-dependent manner with a range of 1.3 – 4.1 fold at week 4 after NT-I7 injection and lasted up to 12 weeks. Thus, 720 mcg/kg was identified as the recommended phase II dose (RP2D). Conclusions: NT-I7 is well tolerated for HGG patients after chemoradiotherapy and has a RP2D of 720 mcg/kg. Immune profiling and cytokine analysis are ongoing and will be updated. The Phase II randomized study to evaluate the effect of NT-I7 vs placebo on ALC and survival is ongoing. Clinical trial information: NCT03687957.

Phase I Study Results of Gimatecan In the Treatment of Myelodysplastic Syndrome (MDS)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1883-1883
Author(s):  
Naveen Pemmaraju ◽  
Hagop Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Stefan Faderl ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Standard Therapy ◽  
Research Funding ◽  
Topoisomerase I ◽  
Clinical Activity ◽  
Hypomethylating Agents ◽  
Monosomy 7 ◽  
Study Results ◽  
Grade 3

Abstract Abstract 1883 Background: Hypomethylating agents (decitabine and 5-azacytadine) are standard therapy for patients (pts) with MDS. Responses are frequently characterized by hematologic improvement with CR rates usually <10%, and responses generally have a median duration of less than 12 months. No standard therapy is available for patients who fail therapy with hypomethylating agents. Topotecan, a topoisomerase I (topo I) inhibitor has previously shown some clinical activity in MDS, although with significant toxicity. We hypothesized that Gimatecan, an oral topo I inhibitor, would be better tolerated, more convenient for patients, and have less toxicity than intravenous topo I inhibitors in treatment of MDS. Objectives: To define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and efficacy of treatment with gimatecan in pts with MDS. Methods: This was a Phase I trial conducted in relapsed/refractory pts failing at least one prior treatment. Inclusion criteria: MDS pts with greater than or equal to 5% blasts or IPSS risk group intermediate (1 or 2) or high (i.e., IPSS 0.5 and higher), age 18 years and older, ECOG PS 0–2, and adequate liver and renal function. Exclusion criteria: Pts who have received only supportive care or transfusions for MDS, pts with prior chemotherapy within 4 weeks of starting study, uncontrolled ongoing systemic illness including congestive heart failure, and women who or pregnant or breast-feeding. Hydroxyurea usage was allowed up to 48 hours prior to start of therapy. Gimatecan was administered orally once daily for 5 days every 28 days. Dose levels explored were 0.6mg, 1.0mg, 1.5mg, and 1.75mg based on a modified Fibonacci schedule. DLTs were monitored as events occurring within first 4 weeks of treatment (1st cycle) and were defined as any non-hematologic grade 3 or 4 toxicity or as grade 33 neutropenia and/or thrombocytopenia with a hypocellular bone marrow and no marrow blasts lasting for 6 weeks or more after the start of a course. All toxicities graded by NCI Common Terminology Criteria 3.0. Results: A total of 16 pts were included. Median age was 62.5 years (range, 37–83). Patients had received a median of 1.5 prior therapies (range,1-5). Cytogenetic analysis revealed: 4 diploid, 4 complex abnormalities, 3 monosomy 7, and 5 with other abnormalities. Median baseline bone marrow blasts prior to enrollment was 5%, with 4 pts having >10%. Baseline neutrophil count was <1×109/L in 8 pts (50%) and platelets <100×109/L in14 pts (88%). IPSS was INT-1 in 7, INT-2 in 6, and High in 3. Six pts had prior malignancies. Only one patient had grade 3 toxicity (mucositis) at a dose of 1.5 mg daily dosing that was considered related to the study drug. No other DLT were observed and an MTD was not defined. The study was ended prematurely because of drug availability. Other toxicities possibly related to gimatecan (all grade 1–2) were: nausea (4), vomiting (2), alopecia, (2) and one each diarrhea, dyspnea, mucositis, peripheral neuropathy, joint pain, and skin rash. Three patients had transient responses, all of them hematologic improvement only: one patient had improvement in hemoglobin and platelets, one in neutrophils and platelets, and one in neutrophils only. There were no pts with CR, CRp/CRn, or PR. Three patients died on study or within one week of discontinuation from study. Conclusions: Gimatecan is well tolerated in patients with MDS but shows minimal clinical benefit for patients with MDS at the doses used. Disclosures: Off Label Use: gimatecan in MDS. Faderl:Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Novartis: Research Funding.

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