Phase II study of 2-methoxyestradiol NanoCrystal dispersion (2ME2) alone and in combination with sunitinib (SU) in patients with metastatic renal cell carcinoma (mRCC) progressing on SU

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16116-e16116
Author(s):  
M. R. Harrison ◽  
R. Pili ◽  
T. Logan ◽  
G. Wilding ◽  
J. Eickhoff ◽  
...  
Keyword(s):  
Disease Progression ◽  
Metabolic Response ◽  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Clinical Activity ◽  
Combination Strategies ◽  
Rational Combination ◽  
Grade 3 ◽  
Number Of Cycles

e16116 Background: Panzem NCD (2ME2) is a non-estrogenic derivative of estradiol with antiproliferative and antiangiogenic activity that downregulates HIF-1α. One mechanism of VEGFR TKI failure may be upregulation of HIF-1α. We hypothesized that 2ME2 may have single-agent activity in pts who previously progressed on SU and that addition of 2ME2 may restore response in pts progressing on SU. Methods: Pts with clear cell mRCC who had previously received or were currently receiving SU with disease progression were eligible. Pts who had previously received SU were treated with 2ME2 alone (arm A). Pts currently on SU continued on the 4:2 schedule, with the addition of 2ME2 (arm B). All pts received 2ME2 at 1,500 mg PO TID, repeated in 6 wk cycles. The primary endpoint was objective response (OR) rate by RECIST. An exploratory endpoint was metabolic response on FDG-PET. Simon optimal 2-stage design was used with plans to enroll 21 pts/arm, and if activity was seen to continue enrollment for a total of 41 pts/arm. Results: 17 pts were enrolled (A: 10; B: 7). Median number of cycles on study was 1 (range <1 to 5). A pt remains on study in cycle 8. Adverse events (AE) of grade 3 or greater occurred in 4 pts (29%). Most frequent AE were: fatigue (71%), diarrhea (50%), dysgeusia (29%), anemia or decreased hemoglobin (29%), and anorexia (21%). Reasons for treatment discontinuation include: disease progression (7), pt/doctor discretion (3), AE (3), and noncompliance (1). No ORs by RECIST were seen. Conclusions: 2ME2 appears to have some single-agent activity, with an MR in a pt removed from study due to AE and a metabolic PR (ΔSUVmax -84%) in a pt with SD by RECIST. With 6/17 pts discontinuing therapy before meeting any OR endpoint, 2ME2 was not tolerable in this population. The study was closed to accrual knowing that a more promising 2ME2 analog is currently under development for oncologic use. The rationale to target HIF-1α after (and during) SU therapy remains of interest. This study design provides a unique way to assess both single-agent and rational combination strategies in pts with mRCC and should be utilized with other agents to seek evidence for clinical activity. [Table: see text]

A phase Ib study of sEphB4-HSA combined with first-line chemotherapy in patients (pts) with advanced pancreatic (PC) and biliary cancers (BC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4640-4640
Author(s):  
Diana L. Hanna ◽  
Syma Iqbal ◽  
Diane Habib ◽  
Denice D. Tsao-Wei ◽  
Afsaneh Barzi ◽  
...  
Keyword(s):  
Objective Response ◽  
Median Number ◽  
Clinical Activity ◽  
First Line ◽  
Cancer Cell Growth ◽  
Prior Therapy ◽  
Common Grade ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Line Chemotherapy

4640 Background: EphB4, a receptor kinase expressed in most epithelial tumors, binds EphrinB2 to affect cancer cell growth, apoptosis and angiogenesis. EphB4 overexpression is associated with advanced stage and shorter survival in multiple cancers. sEphB4-HSA, the albumin-bound extracellular fragment of EphB4, is a first-in-class inhibitor which blocks EphB4-EphrinB2 bidirectional signaling and results in downstream suppression of KRAS, PI3K, and promotes recruitment of CD3 and CD8 T cells into the tumor. The RP2D of sEphB4-HSA is 10 mg/Kg IV q week. Here, we report on sEphB4-HSA in combination with standard first-line chemotherapy. Methods: Pts with advanced PC or BC and no prior therapy for metastatic disease were eligible and enrolled into separate cohorts. Pts with PC received gemcitabine 1,000 mg/m2 + nab-paclitaxel 125 mg/m2 on Days 1, 8, 15 of a 28-day cycle. Pts with BC received gemcitabine 1,000 mg/m2 + cisplatin 25 mg/m2 on Days 1, 8 of a 21-day cycle. sEphB4-HSA 10 mg/kg IV was given weekly starting in Cycle 2. Response was assessed every 2 cycles. Primary endpoint was safety and tolerability; secondary endpoints were objective response rate (ORR) by RECIST 1.1, PFS, OS. Expression of EphrinB2 and EphB4 in tumor was examined by IHC and classified as 1+ (weak staining); 2+ (moderate staining); 3+ (strong, uniform staining). Results: A total of 44 pts with advanced PC (n = 21) and BC (n = 23; 70% gallbladder cancer) were enrolled. Median age 66 yrs; ECOG 1 (70%), 52% male. Median number of cycles received were 5 (PC) and 7 (BC). Median PFS was 5.6 mo in PC and 5.8 mo in BC (95% CI: 3.1-8.1 [PC]; 2.7-7.0 [BC]). Median OS was 7.9 mo in PC and 9.1 mo in BC (95% CI: 6.5-15.0 [PC]; 5.4-15.0 [BC]). In response evaluable pts (20 PC, 22 BC), ORR was 40% in PC (95% CI: 21%, 63%) and 23% in BC (95% CI: 9%, 45%). Stable disease was noted in 48% of PC and 61% of BC pts. The most common grade 3 or 4 treatment-related AEs in ≥10% of pts in both cohorts combined were hypertension (n = 16; 36%), neutropenia (n = 15; 34%), anemia (n = 14; 32%), thrombocytopenia (n = 7, 16%), fatigue (n = 7, 16%). In the PC cohort, there was an association between EphB4 expression and objective response (p = 0.009). Conclusions: sEphB4-HSA has a manageable safety profile in combination with chemotherapy in pts with PC and BC. Clinical activity is manifested by a high disease control rate in both cohorts and a promising RR in PC. Additional biomarker analyses will be presented. Future studies combining chemoimmunotherapy with sEphB4-HSA in pancreatic cancer are planned. Clinical trial information: NCT02495896 .

Nivolumab/pembrolizumab in Child-Pugh grade B/C patients with advanced HCC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16184-e16184
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Li ◽  
Roland Ching-Yu Leung ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Refractory Ascites ◽  
Time To Progression ◽  
Advanced Hcc ◽  
Grade 3 ◽  
Experienced Grade ◽  
Systemic Therapies

e16184 Background: Hepatic derangement commonly accompanies advanced HCC (aHCC) and limits the use of systemic therapies. We aimed to evaluate the use of single agent anti-PD-1 nivolumab or pembrolizumab in Child-Pugh (CP) grade B or C patients with aHCC. Methods: Consecutive aHCC patients with CP grade B (CPB) or C (CPC) liver function who received single agent nivolumab or pembrolizumab were analysed. Objective response rate (ORR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Between May 2015 and June 2020, 61 patients were included. The median age was 60 (range 28-82). 81% and 4.8% had hepatitis-B and hepatitis-C related HCCs respectively. 72.1% (n = 44) were of CPB and 27.9% (n = 17) were of CPC. Amongst CPB patients, 19 (31.1% of all patients) had CP score 7 (CP7) and 25 (41.0% of all patients) had CP score 8 or 9. The median follow-up was 2.3 months. The ORR of CPB and CPC patients were 6.8% and 0% respectively (p = 0.553). The TTP of CPB and CPC patients were 2.1 months (95% C.I. 1.4-2.8) and 1.4 months (95% C.I. 0.6-2.1) respectively (p = 0.204). CPB patients had significantly better OS than CPC patients (3.1 months (95% C.I. 1.4-4.7), vs. 1.7 months (95% C.I. 1.0-2.4), p = 0.041). Compared to CP score ≥8 (CP≥8) patients, CP7 patients had significantly better OS (median OS CP7 6.7 months (95% C.I. 4.0-9.3), vs. CP≥8 1.8 months (1.2-2.4), p = 0.002). Patients with diuretic-refractory ascites had significantly worse OS compared to those without (1.7 months (95% C.I. 1.0-2.5) vs. 3.7 months (95% C.I. 0.1-7.3), p = 0.004). Portal vein (PV) thrombosis was also significantly associated with inferior survival, with median OS of patients with any PV thrombosis being 1.8 months (95% C.I. 1.0-2.5), compared to 5.3 months (95% C.I. 2.4-8.1) of those without (p = 0.004). The median number of doses given was 3 (range 1-34). Median treatment duration was 5.0 weeks (range 0-77). Overall, 25.4% of patients experienced TRAEs and 4.8% experienced grade ≥3 TRAEs. The most common TRAEs were skin-related (13.1%) and constitutional symptoms (6.6%). Conclusions: Nivolumab/pembrolizumab had acceptable safety in CPB/C patients with aHCC. CP7, absence of diuretic-refractory ascites and lack of PV thrombosis were associated with better survival.

Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase 3 trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9500-9500
Author(s):  
Alexander M. Eggermont ◽  
Andrey Meshcheryakov ◽  
Victoria Atkinson ◽  
Christian U. Blank ◽  
Mario Mandalà ◽  
...  
Keyword(s):  
Disease Progression ◽  
Objective Response ◽  
Stage Iv ◽  
Median Number ◽  
Complete Resection ◽  
Stage Iii ◽  
Phase 3 ◽  
Double Blind ◽  
Grade 3 ◽  
To Receive

9500 Background: The phase 3 double-blind EORTC 1325/KEYNOTE-054 trial evaluated pembrolizumab (pembro) vs placebo in stage III cutaneous melanoma patients (pts) with complete resection of lymph nodes. Pembro improved RFS (hazard ratio [HR] 0.57) and DMFS (HR 0.60) (Eggermont, NEJM 2018, TLO 2021). In the pembro group, the incidence of immune related AE (irAE) grade 1-5 was 37%, and of grade 3-5 was 7%. We present the safety profile, response rate and PFS for the subset of pts who had a recurrence and crossed over or were rechallenged with pembrolizumab, within protocol. Methods: Pts were randomized to receive iv. pembro 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year). Upon recurrence with no brain metastases, pts with an ECOG PS 0-2 were eligible to enter part 2 of the study, i.e. to receive pembro 200 mg iv. every 3 weeks for a maximum of 2 years, for crossover (those who received placebo) or rechallenge (those who recurred ≥6 months after completing one year of pembro therapy). Treatment was stopped in case of disease progression (RECIST 1.1) or unacceptable toxicity. Results: At the clinical cut-off (16-Oct-2020), 298 (59%) pts had a disease recurrence in the placebo group; 155 pts participated in the crossover part 2 of the trial. A total of 297 (58%) pts completed the 1-yr pembro adjuvant treatment, of whom 47 had a recurrence ≥6 mths from the stop of treatment and 20 entered in the rechallenge part of the trial. Among 175 pts who started pembro in Part 2, 160 discontinued due to completion of therapy (N=24), disease progression (N=88), toxicity (N=20), investigator's decision (N=21), or other reason (N=7); 15 pts were still on-treatment. Results for the 2 groups are provided in the table. The median number of doses was 12 and 5.5, respectively (resp), and the median follow-up was 41 and 19 mts, resp. Among the 175 pts, 51 (29%) had a grade 1-4 irAE (by group: 47 [30%] and 4 [20%] resp) and 11 (6%) a grade 3-4 irAE. Conclusions: Pembrolizumab treatment after crossover yielded a 39% ORR in evaluable pts and an overall 3-yr PFS of ̃32%, but after rechallenge the efficacy was lower. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA The median PFS (95% CI) from start of Part 2 was 14 (5-27) and 8 (5-15) mts for stage III-resected and III/IV various, resp. Among the 80 stage IV crossover pts with evaluable disease, 31 (39%) had an objective response: 14 (18%) CR, 17 (21%) PR. The 2-yr PFS rate from response was 69% (95% CI 48-83%). For these 80 pts, the median PFS was 6.1 mts and the 3-yr PFS rate was 31% (95% CI 21-41%). Among 9 stage IV rechallenged pts with an evaluable disease, 1 (11%) reached CR, 3 had SD and 5 PD. Clinical trial information: NCT02362594. [Table: see text]

Safety and efficacy of the anti-CD73 monoclonal antibody (mAb) oleclumab ± durvalumab in patients (pts) with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or EGFR-mutant non-small cell lung cancer (EGFRm NSCLC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9047-9047
Author(s):  
Johanna C. Bendell ◽  
Patricia LoRusso ◽  
Michael J. Overman ◽  
Anne M. Noonan ◽  
Dong-Wan Kim ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Objective Response ◽  
Median Number ◽  
Primary Objective ◽  
Ductal Adenocarcinoma ◽  
Clinical Activity ◽  
Expansion Phase ◽  
Human Dose ◽  
Local Immunosuppression ◽  
Grade 3

9047 Background: Upregulation of CD73 in multiple cancers increases adenosine production, leading to local immunosuppression. Oleclumab, a human IgG1λ mAb, inhibits CD73 function and may increase antitumor immunity. Initial data from a Phase I, first-in-human, dose-escalation and expansion study showed that oleclumab ± durvalumab had manageable safety and encouraging clinical activity in pts with advanced CRC or PDAC. We report updated safety and activity in these cohorts and the first results in an expansion cohort of pts with advanced EGFRm NSCLC. Methods: Previously treated pts with histologically or cytologically confirmed microsatellite stable CRC, PDAC, or EGFRm NSCLC received oleclumab 5–40 mg/kg (escalation) and 40 mg/kg (expansion) IV Q2W, alone (escalation only) or with durvalumab 10 mg/kg IV Q2W. The primary objective was safety; secondary efficacy objectives included objective response (OR) per RECIST v1.1 and duration of response (DoR). Results: 66 pts were enrolled in the escalation phase (35 CRC, 31 PDAC) and 126 in the expansion phase (42 CRC, 42 PDAC, 42 EGFRm NSCLC). At data cutoff (DCO; June 9, 2020), the median number of oleclumab doses was 4 in pts on monotherapy (range 1–26) and 4 in pts on combination therapy across both phases (range 1–76). In the escalation phase, there were no DLTs in pts on monotherapy or combination therapy; treatment-related adverse events (TRAEs) occurred in 54.8% of pts on monotherapy (Grade 3–4 in 7.1%) and 54.2% of pts on combination therapy (Grade 3–4 in 20.8%); fatigue was the most common TRAE with both regimens. No TRAEs resulted in death. In previous interim analyses before this DCO, no ORs were reported in the escalation phase. In the expansion phase, 5 pts were treated for ≥12 mos; 6 pts were ongoing at DCO. TRAEs occurred in 54.0% (Grade 3–5 in 15.1%); the most common TRAEs were fatigue (15.1%), diarrhea (9.5%), and rash (7.1%). One pt had a TRAE resulting in death (systemic inflammatory response syndrome). ORs were seen in 1 CRC pt (DoR 35.9+ mos [+ = ongoing response]), 2 PDAC pts (DoR 22.1+ and 28.6+ mos), and 4 EGFRm NSCLC pts (DoR range 5.6 to 15.7+ mos, median not reached; only 1 of the 4 pts had ≥25% programmed cell death ligand-1 [PD-L1]+ tumor cells). Nine CRC pts, 8 PDAC pts, and 9 EGFRm NSCLC pts had SD. Of 6 pts with matched biopsies who received combination therapy, 5 had increases in CD8+ T cells, PD-L1, and granzyme B. Baseline tumor CD73 expression and association with clinical response will be presented. Conclusions: Oleclumab ± durvalumab had a tolerable safety profile and combination therapy showed promising antitumor activity in EGFRm NSCLC. ORs and SD were durable, even in tumor types that are generally immunotherapy-resistant. Clinical trial information: NCT02503774.

A Phase II Study of Temsirolimus (CCI-779) in Patients with Advanced Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4523-4523 ◽  
Author(s):  
Karen W.L. Yee ◽  
Guillermo Garcia-Manero ◽  
Deborah Thomas ◽  
Farhad Ravandi-Kashani ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Blast Crisis ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Median Number ◽  
Prior Therapy ◽  
Flat Dose ◽  
Grade 3

Abstract Temsirolimus (CCI-779, Wyeth Pharmaceuticals) has been shown to inhibit proliferation of a variety of tumors and induce G1 cell cycle arrest by preventing activation of the serine/threonine kinase, mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/Akt pathway. Several lines of evidence implicate the PI3K/Akt/mTOR pathway in hematological malignancies. Interim results of a phase II study evaluating the efficacy and toxicity of single-agent temsirolimus in patients with advanced malignancies are presented. Temsirolimus was administered weekly, at a flat dose of 25 mg, as a 30-minute intravenous infusion. Treatment was continued until evidence of disease progression or unacceptable toxicity. To date, 8 patients have been enrolled and 7 are evaluable for efficacy and toxicity (one patient did not receive temsirolimus). Of these 7 patients, 5 had AML, 1 CML-myeloid blast crisis, and 1 ALL. Median age was 68 years (range, 21 to 87 years) and 5 were male. All patients had received prior therapy, median 2 regimens (range, 1 to 3 regimens). The median number of temsirolimus doses administered was 3 (range, 1 to 10) with a median time on study of 18 days (range, 3 to 89+ days). The most common temsirolimus-related adverse events were grade ≤ 2 and consisted of anorexia, nausea and/or vomiting and diarrhea, mucositis, dermatitis, hypertriglyceridemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia, and fatigue/asthenia. No patient developed nonspecific pneumonitis. Grade 3 toxicities included fatigue/asthenia (2), hyperglycemia (1), painful mucositis with dehydration and electrolyte abnormalities (1), diarrhea with hypokalemia (1), and hypophosphatemia (1). No patient experienced grade 4 toxicities or death from temsirolimus. No patient required dose reductions, but 2 did have dose delays due to grade 3 mucositis (1) and out-of-state hospitalization for pneumonia and atrial fibrillation (1). No patient achieved a complete remission. One patient with heavily pre-treated Philadelphia-negative precursor B-cell ALL had a transient 79% to 91% reduction in peripheral blood blasts 4 days after the first dose of temsirolimus that was maintained for 12 days prior to disease progression with involvement of the synovial fluid in bilateral knees. At the time of analysis, 6 of the 7 patients have discontinued treatment due to disease progression (4), patient refusal (1), or physician decision (1). Preliminary findings indicate that temsirolimus is relatively well-tolerated at a dose of 25 mg per week and may have biologic activity in ALL. Accrual onto the study is currently ongoing.

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.

Irinotecan monotherapy as second-line treatment in advanced pancreatic cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15111-15111 ◽  
Author(s):  
Y. Park ◽  
S. Yi ◽  
H. Kim ◽  
S. Lee ◽  
I. Hwang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stable Disease ◽  
Single Agent ◽  
Advanced Pancreatic Cancer ◽  
Median Number ◽  
Line Treatment ◽  
Second Line ◽  
Best Response ◽  
Grade 3 ◽  
Number Of Cycles

15111 Background: The aim of this phase II study was to determine whether second line therapy with single agent irinotecan could provide any clinical benefit in patients with gemcitabine- pretreated advanced pancreatic cancer. Methods: From January 2004 to October 2006, patients with advanced pancreatic cancer previously treated with gemcitabine alone or combination were treated with single agent irinotecan(150 mg/m2, biweekly), until unacceptable toxicity or disease progression. Primary endpoint was response rate with single stage design. Results: Twenty-eight patients were enrolled(22 male, 6 female, median age : 54.5 years (39–76)). Nine patients are still alive and 3 remain on therapy with stable disease. The median number of cycles was 3.5(1–12). Twenty-four patients were assessable for toxicity and 21 for response. The most common toxicities was diarrhea (grade 3, 12.5%). Grade 3 neutropenia in 1 patient was observed. Other hematological and non-hematological toxicities were mild and manageable. Partial responses were observed in 3 patients (3/21, 14%). An additional 9 patients (9/21, 43%) had stable disease as their best response. 12 patients have progressed with a median time-to-progression of 4.0 months. Conclusions: Single-agent irinotecan was tolerated with manageable toxicity, offering encouraging activity as second-line treatment of patients with advanced pancreatic cancer, refractory to gemcitabine. No significant financial relationships to disclose.

Safety and efficacy of AMG 655 plus modified FOLFOX6 (mFOLFOX6) and bevacizumab (B) for the first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4079-4079 ◽  
Author(s):  
L. Saltz ◽  
J. Infante ◽  
L. Schwartzberg ◽  
J. Stephenson ◽  
C. Rocha-Lima ◽  
...  
Keyword(s):  
Disease Progression ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Objective Response ◽  
Death Receptor ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Death Receptor 5 ◽  
Grade 3 ◽  
Ecog Ps

4079 Background: AMG 655 is an investigational fully human monoclonal antibody (IgG1) agonist of human death receptor 5 (DR5). AMG 655 activates caspases and induces apoptosis in sensitive tumor cells. The primary objective of this phase 1b study was to determine the maximum tolerated dose (up to a target dose of 10 mg/kg IV every 2 weeks) of AMG 655 that can be safely administered in combination with mFOLFOX6-B to mCRC pts. Methods: Eligible pts were ≥ 18 years old with previously untreated mCRC, ECOG PS of 0 or 1, and adequate hematologic, hepatic, and renal function. Pts were enrolled into sequential cohorts of 3- or 10-mg/kg AMG 655 + mFOLFOX6-B administered on day 1 of each 14-day cycle. Study endpoints included incidence of dose-limiting toxicities (DLT), adverse events (AE), pharmacokinetic (PK) parameters of AMG 655, and objective response rate (by modified RECIST). Results: As of 09/08, 12 pts (6 per cohort) were enrolled and received ≥ 1 cycle of treatment; 8 were female. Median (range) age was 54 (37–75), median (range) time on AMG 655 treatment was 6.9 (1.6 to 11.4+) months; 8 pts continue on study treatment. There were no DLTs in the first 28 days of treatment. Eight pts had grade 3–4 AE; the most common were diarrhea, febrile neutropenia, peripheral neuropathy, neutropenia, DVT, and pulmonary embolism (2 pts each). Post baseline laboratory parameters grade ≥ 3: no ALT and AST; 1 grade 3 bilirubin (due to disease progression), and 3 grade 3 lipase (asymptomatic). No anti-AMG 655 antibodies were detected. AMG 655 PK values (Cmax, Cmin) were similar to those observed with single-agent AMG 655 (LoRusso JCO 2007; 25: abstract 3534). AMG 655 did not appear to affect PK of oxaliplatin or bevacizumab. Best overall tumor response: 5 partial responses (2 unconfirmed, both underwent resection); 6 stable disease; 1 pt had non-measurable disease at baseline. Time to disease progression (3 patients): 8, 42, and 44 weeks. Conclusions: The addition of AMG 655 does not appear to substantially alter the safety profile of mFOLFOX6-B. The randomized phase 2 part of the trial (mFOLFOX6-B ± AMG 655) is in progress. [Table: see text]

Phase II study of docetaxel (D) and oxaliplatin (O) in recurrent metastatic transitional cell cancer (mTCC) of the urothelial tract.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 296-296
Author(s):  
Gurkamal S. Chatta ◽  
Leonard Joseph Appleman ◽  
David Friedland ◽  
Gail Tribble ◽  
Diwakar Davar
Keyword(s):  
Stable Disease ◽  
Cell Cancer ◽  
Single Agent ◽  
Objective Response ◽  
Transitional Cell ◽  
Prior Treatment ◽  
Hematological Toxicity ◽  
Disease Stabilization ◽  
Grade 3 ◽  
Number Of Cycles

296 Background: First-line regimens for mTCC of the bladder are either MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or the cisplatinum-gemcitabine doublet. There is no approved second-line option for mTCC. Both single agent D and O have response rates of 10 to 20%, and O in cisplatin-resistant patients (pts). Hence the combination of D and O may be useful in recurrent mTCC. Methods: The combination of D and O was primarily tested for efficacy in recurrent mTCC. All pts had histologically proven TCC with measurable disease, and had prior treatment with at least 1 platinum-containing regimen. D 60 mg/m2 followed by O 110 mg/m2 were administered every 3 weeks. Pts were evaluated for response every 2 cycles and were treated either till progression or for a maximum of 6 cycles. Results: 22 pts were enrolled of whom 19 were evaluable for response. Median age was 72 years (range 44 – 87). All pts had prior treatment with at least 1 cytotoxic regimen, with 8 pts having received 2 or more prior regimens. The mean number of cycles administered was 3. Of the 19 pts evaluable for efficacy, objective response was documented in two pts (both partial responses), three had stable disease, and the remaining fourteen progressed on therapy for an overall disease stabilization rate of 26%. Median time to progression (TTP) was 3.0 months (95% CI 0.2 to 5.8) and median overall survival (OS) was 7.0 months (95% CI 4.6 to 9.4). Toxicity, evaluated in all 22 patients, was relatively mild: grade 3-4 diarrhea in 6 patients, grade 3-4 hematological toxicity in 4 pts and grade 3-4 fatigue in 1 pt. No grade 3-4 neuropathy was observed and no toxic deaths were noted. The median follow-up period was 7.0 months (95% CI 4.5 to 9.5). Conclusions: The combination of D and O is active in previously treated pts with mTCC. This regimen appears to be well tolerated with overall mild toxicity. Whilst this study was not powered for assessing survival, the presence of stable disease in 26% of pts suggests that further investigation of the combination in carefully selected pts maybe warranted.

scholarly journals Phase 2A Study of Copanlisib, a Novel PI3K Inhibitor, in Patients with Indolent Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1701-1701 ◽  
Author(s):  
Martin Dreyling ◽  
David Cunningham ◽  
Krimo Bouabdallah ◽  
Sarit Assouline ◽  
Eric Van den Neste ◽  
...  
Keyword(s):  
Exploratory Study ◽  
Research Funding ◽  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Pi3k Inhibitor ◽  
Aggressive Lymphoma ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Background: Copanlisib is a novel pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with potent preclinical inhibitory activity against both PI3K-d and PI3K-α isoforms. Preliminary results from a phase II study of copanlisib in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) have been reported (Dreyling et al., ASH 2013), with an expansion cohort for patients with aggressive lymphoma still ongoing. We report here the final results of this exploratory study for patients with indolent NHL or CLL treated with copanlisib. Methods: Patients with histologically confirmed indolent NHL or CLL and relapsed or refractory to ≥2 prior lines of treatment were eligible. Copanlisib was administered at a dose of 0.8 mg/kg as a 1 hour intravenous infusion on days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as assessed per independent radiologic review according to the response criteria for lymphoma (Cheson et al., JCO 17:1244,1999) or the guidelines for diagnosis and treatment of CLL (Hallek et al., Blood 111:5446-56, 2008). Secondary endpoints included progression-free survival (PFS) and duration of response (DOR), safety and tolerability. Results: A total of 33 patients were treated in the indolent group, including: follicular NHL (FL) = 16, CLL = 13, marginal zone lymphoma (MZL) = 3, and small lymphocytic lymphoma (SLL) = 1. Median age was 68 years (range 46-89), M/F= 15/18. The median number of previous lines of treatment was 4. Thirty patients (91%) were previously exposed to rituximab. The median number of cycles received was 5.7 (mean 7.2); the median dose and median cumulative dosage of copanlisib administered were 52 mg (87% of planned dose) and 687 mg, respectively. Five patients were dose reduced to 0.6 mg/kg and 1 to 0.4 mg/kg. The ORR as determined by independent radiologic review in 32 evaluable patients was 47%, with 1 CR, 1 uCR, and 13 PRs. By histology, there were 1 CR, 1 uCR and 5 PRs for patients with FL (ORR 47%), and 2/3 PRs for patients with MZL and 1/1 PR for the patient with SLL, for an overall ORR for patients with indolent NHL (excluding CLL) of 53%. The ORR for patients with CLL was 38% (all PRs). Overall, the median DOR was 287 days (95% CI: 56; not yet reached); median PFS was 240 days (95% CI: 173; 419). The most common adverse events (AEs) of all grades were hyperglycemia (70%), hypertension (70%), fatigue (64%), diarrhea (36%), neutropenia (36%) and anemia (33%). Grade 3-4 AEs occurring in >10% of patients included: hypertension (49% grade 3), neutropenia (30%), hyperglycemia (30% grade 3), and anemia (15%). Dose reductions, interruptions, or permanent discontinuations due to AEs were reported in 4 (12%), 21 64%), and 11 (33%) patients, respectively. There was one drug-related grade-5 event; meningitis in a heavily-pretreated CLL patient with longstanding disease-related immunodeficiency, occurring shortly after first administration of copanlisib. Conclusions: Copanlisib is active as a single-agent in heavily pretreated, advanced refractory/relapsed FL, MZL, SLL, and CLL. Copanlisib exhibited an acceptable toxicity profile, consistent with previous reports. Based on the results of this exploratory study, a phase 2B study of copanlisib in relapsed or refractory indolent NHL (after prior treatment with an alkylating agent and rituximab) has been initiated and is ongoing. Disclosures Dreyling: Bayer HealthCare: Scientific advisory board/consultant Other. Cunningham:Roche: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Merck Serono: Research Funding; Novartis: Research Funding; Astra Zeneca: Research Funding. Giurescu:Bayer Pharma AG: Employment. Mappa:Bayer S.p.A.: Employment. Grunert:Bayer Pharma AG: Employment. Childs:Bayer HealthCare Pharmaceuticals: Employment.

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