SAINT: Results of a phase 1/2 study of safety/efficacy using safe amounts of ipilimumab, nivolumab, and trabectedin as first-line treatment of advanced soft tissue sarcoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11016-11016 ◽  
Author(s):  
Erlinda Maria Gordon ◽  
Victoria S. Chua-Alcala ◽  
Katherine Kim ◽  
Seiya Liu ◽  
Nicole Angel ◽  
...  
Keyword(s):  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Safety Analysis ◽  
Phase 2 ◽  
First Line ◽  
Efficacy Analysis ◽  
First Line Therapy ◽  
Pre Treatment ◽  
Grade 3

11016 Background: Sarcoma cells are most immunogenic earlier in the disease course and prior to treatment when the immune system can recognize and destroy them. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first line therapy. Methods: This is an IRB-approved dose-seeking Phase 1/2 protocol using defined doses of I (1 mg/kg i.v. q 12 weeks), N (3 mg/kg i.v. q 2 weeks) and escalating doses of T (1.0, 1.2, 1.5 mg/m2 i.v. q 3 weeks), employing the “Cohort of Three” design, followed by a Phase 2 using the MTD of trabectedin. Results: Nine subjects were treated in Phase 1 of the study, and 31 subjects in Phase 2. Safety analysis: at Dose 1: Grade 3 treatment-related adverse events (TRAEs) included fatigue (n = 1), increased TSH (n = 1). At Dose 2, Grade 4 TRAEs included thrombocytopenia with bleeding, DLT (n = 1), increased CK (n = 1); Grade 3 TRAEs included anemia (n = 1), myalgia (n = 1), increased TSH (n = 1), decreased TSH (n = 1), increased AST (n = 1). Efficacy analysis (evaluable patients): At Dose 1: Disease Control Rate (DCR = CR, PR, SD) was 67%, median PFS, 18 weeks; median OS, 50 weeks; At Dose 2: PR (n-1), DCR 60%, median PFS, 24 weeks; median OS, > 46 weeks. At Phase 2, MTD Dose 2 (PUPs): Safety analysis (n = 31): Grade 3 TRAEs included fatigue (n = 2), increased ALT (n = 6), increased AST (n = 4), hypernatremia (n = 1), hyponatremia (n = 1), dehydration (n = 1), rash (n = 1), port cellulitis (n = 1), psoriasis exacerbation (n = 1), increased TSH (n = 1), decreased hemoglobin (n = 2), neutropenia (n = 1). Efficacy analysis (N = 23 evaluable): PR (n-5; 2 UPS, 1 synovial sarcoma, 1 liposarcoma, 1 leiomyosarcoma,), BORR 22%, DCR 96%. Median PFS and OS not yet reached. After 4 treatment cycles, one resected tumor showed 80% necrosis and a greater number (30%) of CD8+ killer T cells, in the TME compared to archived pre-treatment tumor. Conclusions: These data suggest that the SAINT protocol (1) is safe with manageable adverse events, with no additive toxicity, and (2) may control tumor growth. Phase 2 of the study is on-going. Clinical trial information: NCT03138161.

The SAINT: Initial results of a phase I/II study of safety/efficacy using safe amounts of ipilimumab, nivolumab, and trabectedin as first-line treatment of advanced soft tissue sarcoma.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 22-22
Author(s):  
Sant P. Chawla ◽  
Victoria S. Chua-Alcala ◽  
Katherine Kim ◽  
Nupur Assudani ◽  
Ahmad Al-Shihabi ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Adverse Events ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Soft Tissue Sarcomas ◽  
Phase 2 ◽  
First Line ◽  
Surgical Specimen ◽  
Grade 3

22 Background: Sarcoma cells are most immunogenic at the onset of cancer. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first line therapy. Objectives: (1) To evaluate the safety of ipilimumab (I), a CTLA4 inhibitor, nivolumab (N), a PD-1 inhibitor, and escalating doses of trabectedin (T), a marine-derived natural alkaloid, in advanced soft tissue sarcomas (STS), (2) To investigate the BORR, DCR, PFS and OS, and (3) to correlate response with immune cell trafficking in the tumor microenvironment. Methods: This is an IRB-approved dose-seeking phase 1/2 study using defined doses of I (1 mg/kg IV q 12 weeks), N (3 mg/kg IV q 2 weeks) and escalating doses of T (1.0, 1.3, 1.5 mg/m2 IV q 3 weeks), employing “cohort of three” design, with a Phase 2 component using the MTD of T. Results: Phase 1 safety analysis: At Dose 1: Grade 3 treatment related adverse events (TRAEs): fatigue (n = 1), increased TSH (n = 1). At Dose 2, Grade 4 TRAEs: thrombocytopenia with bleeding, DLT (n = 1), increased CK (n = 1); Grade 3 TRAEs: anemia (n = 1), myalgia (n = 1), increased TSH (n = 1), decreased TSH (n = 1), increased AST (n = 1). At Phase 2, Grade 4 TRAEs: increased CK (n = 1); Grade 3 TRAEs: increased ALT (n = 4), anemia (n = 3) neutropenia (n = 1), portal cellulitis (n = 1). Efficacy analysis: Phase 1 (n = 9): At Dose 1: DCR 67%, median PFS, 18 weeks; median OS, 50 weeks; At Dose 2: PR (n-1, rhabdomyosarcoma), DCR 60%, median PFS, > 42 weeks; median OS, > 47 weeks. Phase 2 (n = 16): PR (n = 3; 1 liposarcoma, 1 leiomyosarcoma, 1UPS); BORR 18.75%, DCR 87.5%, median PFS, > 19 weeks; median OS, > 26 weeks. Surgical resection was undertaken in 1 patient with SD after 4 cycles. The surgical specimen showed 80% necrosis and greater number (30%) of CD8+ killer T cells, 10% PD-L1+ cells in the TME compared to that of archived pre-treatment tumor. Conclusions: Taken together, these data suggest that the SAINT protocol (1) is safe with manageable adverse events, with no additive toxicity, and (2) may control tumor growth. The phase 2 part of the study is on-going. Clinical trial information: NCT03138161.

Phase 1/2 study of safety/efficacy using trabectedin, ipilimumab, and nivolumab as first-line treatment of advanced soft tissue sarcoma (STS).

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS46-TPS46 ◽  
Author(s):  
Erlinda Maria Gordon ◽  
Victoria S. Chua-Alcala ◽  
Katherine Kim ◽  
William W. Tseng ◽  
Doris M Quon ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Categorical Variables ◽  
Phase 2 ◽  
First Line ◽  
First Line Therapy ◽  
Number Of Patients

TPS46 Background: Sarcoma cells are most immunogenic at the onset of cancer when the immune system can recognize and destroy them. Hence, immune checkpoint inhibitors would be most effective when given as first line therapy. Objectives: (1) To investigate the maximum tolerated dose of trabectedin, an alkylating agent, when given sequentially with ipilimumab, a CTLA4 inhibitor, and nivolumab, a PD-1 inhibitor, in advanced STS, (2) To investigate the objective response rate (ORR), progression free survival (PFS) and overall survival (OS) , and (3) To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: Forty patients ≥18 years of age with advanced STS will be enrolled. This is a phase 1/2 study using a defined dose of ipilimumab (1 mg/kg i.v. q 12 weeks), nivolumab (3 mg/kg i.v. q 2 weeks), and escalating doses of trabectedin (1.0, 1.3, 1.5 mg/m2 i.v. q 3 weeks). I. Dose Escalation Phase 1 (previously treated patients): The study will employ the standard “cohort of three” design. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. II. Expansion Phase 2 (previously untreated patients): An additional 22-28 patients will receive trabectedin at the MTD and defined doses of ipilimumab and nivolumab to assess overall safety and potential efficacy in a greater number of patients. Patients may continue treatment until significant disease progression or unacceptable toxicity occurs. Statistical Considerations: NIH CTCAE v4.03 and RECIST v1.1 will be used. Categorical variables will be summarized by the n and percent in each category. Point estimates for efficacy endpoint incidences will be accompanied by a 2-sided 95% exact binomial CI. Time to event endpoints will be summarized descriptively using the KM method. The analyses of all study objectives will be descriptive and hypothesis generating, for planning Phase 2/3 studies. Clinical trial information: NCT 03138161.

CHOP-R (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, Rituximab) Compared to CPOP-R (Cyclophosphamide, Pixantrone, Vincristine, Prednisone, Rituxamib) in First-Line Therapy of Diffuse Large B Cell Lymphoma (DLBCL): An Interim Analysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3445-3445 ◽  
Author(s):  
Raoul Herbrecht ◽  
Stephen Couban ◽  
Florian Weissinger ◽  
Igor Gorbatchevsky ◽  
Richard H. van der Jagt
Keyword(s):  
Heart Failure ◽  
Adverse Events ◽  
Interim Analysis ◽  
Phase 1 ◽  
Safety Data ◽  
B Cell Lymphoma ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade 3

Abstract The CHOP-R regimen is the standard regimen for first-line therapy of patients with DLBCL. Pixantrone (BBR 2778) is a novel aza-anthracenedione with structural similarities to mitoxantrone. In a phase 1/2 study of CPOP in 65 patients with relapsed NHL who had received a first-line anthracycline-containing regimen, patients received pixantrone at 80–180 mg/m2. This study indicated substantial activity with an overall response rate of 77% and complete response (CR) rate of 54% with acceptable toxicity. Studies in indolent NHL demonstrated that the combination of pixantrone with rituximab is well tolerated and more active than rituximab alone (JCO, 24(18S), 2006:7578). To evaluate the safety and activity of CPOP-R with special regard to cardiac safety in the first-line setting, a randomized phase 2 study in untreated patients with DLBCL comparing CPOP-R to CHOP-R is being conducted. Patients with untreated, histologically confirmed CD20-positive DLBCL receive CHOP-R or CPOP-R every 21 days for 6–8 cycles. An interim analysis for efficacy was prospectively planned to be performed when 40 patients had completed 4 cycles of therapy to test whether the CR rate of CPOP-R (pixantrone dose of 150 mg/m2) is, with 95% confidence, not more than 15% less than the CR rate of CHOP-R. We report the results of this analysis, which included 40 patients (21 CPOP-R and 19 CHOP-R) who had completed 4 cycles or had prematurely withdrawn from the study. Preliminary safety data (CPOP-R=27 patients, CHOP-R=30 patients) were also evaluated. CR rates after 4 cycles based on investigators’assessment were similar between arms (CPOP-R=33%, CHOP-R=37%). In general, adverse events were equal between arms. There were no more grade 3–4 adverse events (41% CPOP-R vs 50% CHOP-R) and no more grade 3–4 treatment-related adverse events (33% in CPOP-R vs 40% in CHOP-R) in the CPOP-R arm compared to the CHOP-R arm. 8 patients in each arm had asymptomatic absolute LVEF declines of ≥10%. 3 patients in the CPOP-R arm had a LVEF decline of >15% and ≤20% compared to 5 patients in the CHOP-R arm. No patients in the CPOP-R arm had a >20% LVEF decline compared to 2 patients in the CHOP-R arm. No heart failure or deaths resulting from heart failure have been reported. Infections reported as serious adverse events occurred in 1 patient (4%) in the CPOP-R arm and 3 patients (10%) in the CHOP-R arm. Grade 3–4 neutropenia was similar (CPOP-R = 34%, CHOP-R = 30%). Febrile neutropenia was less frequent in the CPOP-R arm (4% vs 23%). There were 2 deaths within 30 days of the last dose of study drug on CPOP-R arm. Both patients were > 80 years; 1 of the events was attributed to study treatment secondary to neutropenic infection. No deaths were reported in the CHOP-R arm. Based on this preliminary analysis, we conclude that for 1st-line therapy of patients with DLBCL, CPOP-R has similar activity to CHOP-R with no more toxicity. Further follow-up is required.

191 Association of immune related adverse events with the efficacy of immune checkpoint inhibitors in metastatic renal cell carcinoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A205-A206
Author(s):  
Vasilii Bushunow ◽  
Leonard Appleman ◽  
Roby Thomas
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Kaplan Meier

BackgroundImmune checkpoint inhibitors (ICI) are first-line therapy for tumors including metastatic renal cell carcinoma (mRCC). Use of ICI is complicated by diverse immune-related adverse events (irAEs), which can add significant morbidity but are also associated with improved efficacy of therapy.1 2 Risk factors for development of irAE are still poorly understood. We hypothesized that patients with mRCC treated with ICI as first-line therapy have higher rates of developing irAE’s than patients previously treated with other therapies.MethodsWe conducted a single-institution, retrospective medical record review of patients with mRCC treated with immune-checkpoint inhibitors from March 2011 through April 15, 2020. We identified therapy duration, and presence, severity, and treatment of adverse events. We defined overall survival as time elapsed from date of diagnosis until death or until completion of study. We classified severity of adverse events according to CTCAE guidelines. Statistical methods included univariate Cox proportional hazards and logistic regression models, and Kaplan-Meier curves were plotted for subgroups.ResultsA total of 64 unique charts were reviewed. 18 patients (28%) of patients were treated with ICI as first-line therapy. 28 patients (44%) experienced immune-related adverse events with a total of 40 irAE’s identified. Most irAE were grade I-II (78%), with 7 (17%) grade III and 1 (2.4%) grade IV irAE’s. Most common sites were skin (29%), thyroid (20%) and gastrointestinal (15%). Patients with irAE had increased survival compared to those who did not have irAE (median survival not reached, vs 139 weeks, p=0.0004) (figure 1). This finding remained after excluding patients who had only experienced dermatologic irAE (median survival not reached in non-derm irAE subgroup, vs 144 weeks for dermatologic or no irAE, p=0.01) (figure 2). Patients treated with ICI as first line therapy had greater rates of developing irAE (72%) than those who had prior therapies (32%) (OR 5.4; p = 0.006). There was no association between histology type and rate of irAE.Abstract 191 Figure 1Kaplan-Meier survival plot of OS between patients with any irAE and those without any irAEAbstract 191 Figure 2Kaplan-Meier survival plot of OS between patients with non-dermatologic irAE and those without any irAE or only dermatologic irAEConclusionsThe development of irAE’s in patients with mRCC treated with ICI is associated with longer survival. This study joins the growing body of evidence showing that presence of irAE’s is associated with increased treatment efficacy. Use of ICI as first-line therapy is associated with higher risk of irAE. Given growing use of ICI as first-line therapy, further study to predict onset and severity of irAE’s is required.AcknowledgementsHong Wang, PhD, for statistical support.Ethics ApprovalThis study was approved by the University of Pittsburgh Institutional Review Board. Approval number STUDY19100386.ReferencesElias R, Yan N, Singla N, Levonyack N, Formella J, Christie A, et al. Immune-related adverse events are associated with improved outcomes in ICI-treated renal cell carcinoma patients. J Clin Oncol 2019;37(7):S645.Verzoni E, Cartenì G, Cortesi E, et al. Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program. J Immunother Cancer 2019;7(1):99.

Phase 1/2 Trial Of Lenalidomide In Combination With Cyclophosphamide and Prednisone (REP) In Patients With Lenalidomide-Refractory Multiple Myeloma (REPEAT-study)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 287-287 ◽  
Author(s):  
Inger S. Nijhof ◽  
Sonja Zweegman ◽  
Mark-David Levin ◽  
Harry R. Koene ◽  
Aart Beeker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Oral Cyclophosphamide ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Grade 3 ◽  
Dose Levels

Abstract Background The outcome of multiple myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide (LEN) and bortezomib (BORT) is very poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012; 26;149-157). We have previously shown in a small retrospective study that the combination of continuous low dose oral cyclophosphamide (endoxan) and prednisone combined with lenalidomide (REP) had remarkable activity in heavily pretreated LEN-refractory multiple myeloma patients (median 6 lines of previous chemotherapy) (vd Donk et al; Br J Haematol 2010;148(2):335-7). To determine the optimal dose of lenalidomide with continuous cyclophosphamide and prednisone, we initiated a prospective study to evaluate the maximum tolerated dose (MTD) of the REP regimen and to assess its efficacy and safety in LEN-refractory MM patients. Here we report safety and efficacy data from the phase 1 dose-escalation part of the REPEAT-study (NCT01352338). Patients and Methods Patients aged ≥ 18 years with LEN-refractory MM, ECOG-performance status 0-3 and adequate kidney, liver and hematologic function were included. Five dose levels were evaluated using a standard 3+3 design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Patients received LEN in doses ranging from 10-25 mg/day on days 1-21 of 28-day cycle, while oral cyclophosphamide (50 or 100 mg) and prednisone (20 mg) were given continuously. Therapy was continued until progression. The MTD for the phase 2 part is defined as the highest dose level with 0 or 1 DLT's observed in 6 patients. Results Up till now, 35 patients were enrolled (22 in phase 1 and 13 in phase 2) from August 2011 to June 2013. The phase 2 part is still recruiting and data are not evaluable yet. One patient in phase 1 was excluded because of study violation and is not included in the analysis. The median age of the 21 evaluable patients in phase 1 was 69 years (range 41-73); 76% were male. The median duration of the disease from diagnosis was 41 months (range 18-96), median number of prior therapies was 3 (range 2-6), and 12 patients (57%) had previously received autologous SCT. All patients were LEN-refractory, 19 (90%) had prior BORT treatment, and 16 (76%) had BORT-refractory MM. Fifty-five % of the patients were considered high risk by FISH. At the time of analysis, 16 of 21 patients in phase 1 have discontinued treatment because of disease progression (13), alternative treatment (allo-SCT) (1), or adverse events (2). The MTD was defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously (dose level 4), based on three patients experiencing a DLT: two developed pneumonia (in dose levels 4 and 5; CTC grade 3), and one patient at dose level 5 experienced CTC grade 3 dyspnea. Neutropenia (18%) and thrombocytopenia (18%) were the most common grade 3 hematological adverse events (AEs), which were managed with growth factor support and/or dose modification. There were no grade 4 hematologic AEs. Grade 3 respiratory tract infections (29%) and grade 2 fatigue (19%) were the most common non-hematological AEs. Venous thromboembolism occurred in 1 patient. Figure 1 shows a waterfall plot of the responses of the patients that participated in the phase 1 part of the study. Overall response rate (≥ PR) was 67% with 6 out of 21 (29%) patients achieving at least VGPR. In addition 2 patients achieved MR (≥ MR: 76%). Median PFS and OS were 6.3 and 15.5 months respectively. Similar results were achieved in the subset of patients with LEN- and BORT-refractory disease. Interestingly, laboratory experiments with purified myeloma cells from these patients suggest synergism between LEN and cyclophosphamide. Conclusions The REP regimen induces high response rates and prolonged PFS and OS in LEN-refractory patients with acceptable toxicity. The MTD is defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously. Phase 2 is enrolling patients and evaluates efficacy and safety of the REP regimen at the MTD. REP should be considered a valuable salvage option for LEN-refractory MM patients. We will present an updated follow-up at ASH. Disclosures: Sonneveld: Onyx: Research Funding; Millenium: Research Funding; Janssen-Cilag: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. van de Donk:Celgene: Research Funding.

Safety of epacadostat 100 mg bid plus pembrolizumab 200 mg Q3W in advanced solid tumors: Phase 2 data from ECHO-202/KEYNOTE-037.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3012-3012 ◽  
Author(s):  
Omid Hamid ◽  
Todd Michael Bauer ◽  
Alexander I. Spira ◽  
David C. Smith ◽  
Anthony J. Olszanski ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
Phase 3 ◽  
Indoleamine 2 ◽  
Safety Population ◽  
Common Grade ◽  
Grade 3

3012 Background: The immunosuppressive enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) facilitates immune tolerance in cancer via T-cell suppression, and IDO1 overexpression is associated with poor survival. Epacadostat, an oral inhibitor of IDO1, has been shown to be well tolerated as monotherapy and in combination with checkpoint inhibitors. ECHO-202/KEYNOTE-037 is a phase 1/2 study evaluating the safety and efficacy of oral epacadostat plus IV pembrolizumab in patients (pts) with advanced tumors. Based on phase 1 outcomes, epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was selected for phase 2 evaluation. This analysis summarizes phase 2 safety experience in the overall population of ECHO-202/KEYNOTE-037 (pooled across tumor types) at an October 29, 2016 data cutoff. Methods: Phase 2 pts were ≥18 years of age with advanced or recurrent melanoma (MEL), non–small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma (UC), triple-negative breast cancer, squamous cell carcinoma of head and neck (SCCHN), ovarian cancer, diffuse large B-cell lymphoma, or microsatellite instability–high colorectal cancer. Results: The overall safety population comprised 244 pts receiving ≥1 study treatment dose. Median age was 63 years, 52% were women, and 91% were white. As of data cutoff, 134 study pts (55%) discontinued study treatment, primarily due to disease progression (n = 97). Median exposure to study treatment was 86 days (range, 1–374 days). TRAEs occurring in ≥5% of pts were fatigue (23%); rash (16%); diarrhea and nausea (7% each); increased alanine aminotransferase, increased aspartate aminotransferase, and pruritus (6% each); and pyrexia (5%). A total of 37 pts (15%) had grade ≥3 TRAEs; the most common grade ≥3 TRAEs were increased lipase (asymptomatic) and rash (3% each). TRAEs led to discontinuation in 3% of pts. Conclusions: Epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was associated with an acceptable safety profile in pts with advanced cancers, supporting continued evaluation of the combination. The phase 3 ECHO-301/KEYNOTE-252 MEL study is ongoing and additional phase 3 studies (NSCLC, UC, RCC, SCCHN) are planned. Clinical trial information: NCT02178722.

Results of the phase Ib portion of a phase I/II trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreatic cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 452-452 ◽  
Author(s):  
Nathan Bahary ◽  
Ignacio Garrido-Laguna ◽  
Andrea Wang-Gillam ◽  
Asha Nyak-Kapoor ◽  
Eugene Kennedy ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trial ◽  
Immune Tolerance ◽  
Phase 1 ◽  
Underlying Disease ◽  
Metastatic Pancreatic Cancer ◽  
Phase 2 ◽  
First Line ◽  
Dose Cohort ◽  
Grade 3

452 Background: IDO is a tryptophan-catabolizing enzyme that plays a key role in the normal regulation of peripheral immune tolerance. Tumors also employ this mechanism to induce a state of immunosuppression. In cancer, IDO mediates an acquired immune tolerance towards tumors, allowing evasion of immune mediated destruction. Indoximod is a broad IDO pathway inhibitor, as it has been shown to potentially interfere with multiple targets within the IDO pathway. Pre-clinical models have demonstrated synergy between indoximod and chemotherapy. The combination of gemcitabine (Gem) and nab-paclitaxel (Nab) is a current SOC for first line treatment of metastatic pancreas cancer. This trial is designed to determine the potential for benefit of combination therapy with indoximod and Gem / Nab for to patients with metastatic pancreatic cancer. Methods: Indoximod was escalated (600mg/1000mg/1200mg PO twice daily continuous dosing) in combination with Gem / Nab (1000mg/m2 / 125mg/m2 q week x 3 per 4 week cycle) in a 3+3 design. Patients were first line metastatic pancreatic cancer or minimum 6 months from adjuvant chemo and / or radiation following previous resection. Treatment continues until progression or toxicity. Primary endpoints for Phase 1 include safety, toxicity, and determination of a Phase 2 dose. The prospective collection of tumor samples for exploration of biomarkers is built into the trial. Results: 15 patients were required to successfully dose escalate the Phase 1 study to 1200 mg twice daily. Two patients were replaced in the lowest dose cohort after rapid deterioration due to underlying disease during the regimen limiting toxicity (RLT) window. One RLT was observed during the study (ascites Grade 3) at the highest dose cohort. The most common AE’s (all Grade 1 or 2) occurring in ≥ 4 subjects, regardless of attribution, were nausea, fatigue, peripheral edema, peripheral neuropathy, alopecia. Conclusions: Indoximod and Gem / Nab were well tolerated in a clinical trial setting. The Phase 2 dose was set at 1200 mg twice daily and Phase 2 enrollment (target 80 patients) is ongoing. Updated results will be presented. Clinical trial information: NCT02077881.

A phase I/II investigation of nivolumab and ABI-009 (nab-sirolimus) in advanced undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), chondrosarcoma (CS), osteosarcoma (OS), and Ewing sarcoma: Preliminary efficacy and safety results.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11057-11057 ◽  
Author(s):  
Erlinda Maria Gordon ◽  
Victoria S. Chua-Alcala ◽  
Katherine Kim ◽  
Rekha Baby ◽  
Nicole Angel ◽  
...  
Keyword(s):  
Dose Level ◽  
T Cell Activation ◽  
Ewing Sarcoma ◽  
Mtor Inhibitor ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Synergistic Activity ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Grade 3

11057 Background: Immune checkpoint inhibitors that promote sustained T cell activation may have synergistic activity with an mTOR inhibitor. This phase 1/2 study is aimed to investigate if ABI-009 a novel albumin-bound mTOR inhibitor is feasible and improve clinical outcomes in combination with nivolumab. Methods: Eligible patients with advanced UPS, LPS, CS, OS, or Ewing sarcoma are treated with the standard dose of nivolumab (240 mg given IV every 3 weeks, Day 1 of every 21-day Cycle). ABI-009 will be given IV on Days 8 and 15 of each cycle starting on Cycle 2 following the 2nd nivolumab dose. Phase 1 portion is a dose-finding study using the 3+3 design. The starting dose of ABI-009 is 56 mg/m2, and sequentially escalating doses are 75 and 100 mg/m2. The primary endpoint is to identify the maximum-tolerated dose (MTD) of ABI-009 + nivolumab, secondary endpoints include disease control rate, progression-free survival (PFS), and overall survival (OS). Exploratory endpoints include correlation of PFS and OS with PD-L1 and other biomarkers. The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: 9 patients were treated in Phase 1 (n = 3 each dose level); 5/9 patients had OS, 3/9 CS, and 1 had Ewing sarcoma. No dose-limiting toxicities (DLTs) were observed, the MTD was not reached, and 100 mg/m2 ABI-009 was designated as the recommended phase 2 dose. Safety analysis: At Dose 1: Grade 3 treatment-related adverse events (TRAEs) included hyper dyslipidemia (n = 1), and hyperglycemia (n = 1). At Dose 2: Grade 3 TRAEs included increased ALT (n = 1). At Dose 3: Grade 3 TRAEs included hypophosphatemia (n = 1). Seven of 9 patients have discontinued treatment: 5 patients due to PD, 2 with SD opted to stop treatment due to drug-related Grade 2 AEs (pruritus, acneiform rash, and 2 with SD are still on therapy at Dose 3. The median PFS at dose level 3 has not yet been reached. Conclusions: The MTD was not reached and Dose 3 (100 mg/m2) has been designated as the phase 2 dose of ABI- 009, combinable with nivolumab. Enrollment to phase 2 is ongoing. Clinical trial information: NCT03190174.

AK104 (PD-1/CTLA-4 bispecific) combined with chemotherapy as first-line therapy for advanced gastric (G) or gastroesophageal junction (GEJ) cancer: Updated results from a phase Ib study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 232-232
Author(s):  
Jiafu Ji ◽  
Lin Shen ◽  
Ziyu Li ◽  
Nong Xu ◽  
Tianshu Liu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Neutrophil Count ◽  
Checkpoint Inhibitors ◽  
Gastroesophageal Junction ◽  
Tumor Infiltrating Lymphocytes ◽  
First Line ◽  
Significant Treatment ◽  
Phase Ib ◽  
First Line Therapy ◽  
Grade 3

232 Background: OS and PFS benfits have been observed in combination of anti-PD-1 agent plus chemotherapy compared to chemotherapy alone as first-line advanced G/GEJ cancer (Checkmate-649). It uncovers the significant treatment prospects of immune checkpoint inhibitors combination therapies. The PD-1/CTLA-4 dual blockade has consistently demonstrated higher response rate compared to PD-1 monotherapy but higher toxicity. AK104, a PD-1/CTLA-4 bispecific antibody, is designed as a novel tetrameric form. It could preferentially binds to tumor-infiltrating lymphocytes (TILs) co-expressing PD-1 and CTLA-4 with higher avidity in the tumor micro-environment than peripheral sites. Therefore, AK104 is designed to retain the efficacy benefit derived from the combination of anti-PD-1 and anti-CTLA-4 while conferring superior safety compared to the co-administration of these individual agents. This Phase Ib study evaluates the safety and efficacy of AK104 and mXELOX in the first-setting of G/GEJ cancer cohorts (NCT03852251). Methods: Pts with untreated, inoperable advanced G/GEJ adenocarcinoma regardless of PD-L1 status were enrolled to cohorts of 3-6 pts at AK104 doses of 4, 6 and 10 mg/kg q2w + mXELOX [oxaliplatin 85 mg/m2 and capecitabine 1000 mg/m2] during dose escalation. Selected cohorts were expanded up to 18 pts to further establish the recommended Phase II dose. Tumor tissue for determination of PD-L1 status with combined positive score (CPS) must be provided from ≤ 6 months before study treatment. Antitumor activity was assessed by RECIST v1.1. Results: As of Sep 9, 2020, 34 pts (73.5% male, median age 63.1 yrs [29-75], 76.5% G and 23.5% GEJ ) have received AK104 at doses of 4 mg/kg (n = 18), 6 mg/kg (n = 14) and 10 mg/kg (n = 2) + mXELOX. AK104-related adverse events (TRAEs) occurred in 79.4% of pts. G3 TRAEs occurred in 29.4% (10/34) and no G4 or G5 TRAE was reported. Most frequent TRAEs (incidence ≥ 15%) were neutrophil count decreased (26.5%), platelet count decreased (20.6%), white blood cell count decreased (17.6%), anaemia (17.6%) and infusion related reaction(17.6%). Grade ≥3 TRAEs reported in ≥2 pts were neutrophil count decreased (8.8%). Grade ≥3 immune-related AEs were reported in 8.8% of pts (hepatitis, pneumonitis, hyponatraemia). Of 24 pts evaluable for antitumor activity, ORR was 66.7% (95% CI 44.7, 84.4 ) including 2 CRs and 14 PRs . The disease control rate (DCR) was 95.8% (95% CI 78.9, 99.9). Response was seen regardless of PD-L1 status. At a median follow-up of 8.6 mons for the 4mg/kg cohort, 6-mons PFS rate was 69.5% (95%CI 41.3, 86.1). Conclusions: AK104 in combination with mXELOX had a manageable safety profile and encouraging antitumor activities in pts with advanced G/GEJ adenocarcinoma regardless of PD-L1 status. Enrollment is currently ongoing for 6 mg/kg and 10 mg/kg cohort. Clinical trial information: NCT03852251.

Combination of immunotherapy and tyrosine kinase inhibitor in first-line metastatic renal cell carcinoma: A real-world Indian experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16576-e16576
Author(s):  
Amit Rauthan ◽  
Poonam Patil ◽  
Nitin Yashas Murthy ◽  
SP Somashekhar ◽  
Shabber Zaveri ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade 3

e16576 Background: Immuno-oncology (IO) agents in combination with oral tyrosine kinase inhibitors (TKIs) has become a standard first line therapy in metastatic renal cell carcinoma (mRCC) patients. Various combinations such as pembrolizumab + axitinib, avelumab + axitinib, nivolumab + cabozantinib and pembrolizumab + lenvatinib have all shown better results than sunitinib. There is very limited data about this from India. Methods: This is a single center, retrospective study of mRCC patients, who received first line treatment was nivolumab or pembrolizumab with axitinib or lenvatinib. The endpoints were objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AE). Results: Between Jan 2019 to Jan 2021, 22 patients were treated with IO + TKI combination. 12 patients received axitinib, and 10 lenvatinib. Age range was 35 to 78 years with 18 males and 4 females. IMDC risk stratification showed 3 favorable (13.6%), 13 intermediate (59%) and 6 poor risk (27.2%) patients. 2 patients (9%) achieved complete response(CR), 13 (59%) partial response (PR), 4 (18.2%) had stable disease and 3 (13.6%) progressed. The ORR was 68%. Median PFS was 22 months (1 month- 24 months). OS at 1 year was 92%, and median OS was not reached. Grade 3/4 immune related adverse events (AEs) were seen in 3 (14.2%) patients (1 colitis,1 pneumonitis,1 encephalitis), for whom the IO was discontinued. TKI related grade 3/4 AEs were seen in 8 patients (38%), and were managed with dose reductions. Conclusions: Combination IO + TKI is a very effective first line therapy in mRCC. An ORR of 68%, median PFS of 22 months and 1 year OS of 92% is the best we have seen in our patients. The efficacy of this combination is seen in all IMDC subgroups. The combination is well tolerated, and the TKI AEs are comfortably managed with dose reduction. IO combinations should be preferred over single agent TKIs (sunitinib or pazopanib) as first line therapy.

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