Gilteritinib Clinical Activity in Relapsed/Refractory FLT3 Mutated AML Previously Treated with FLT3 inhibitors

2022 ◽  
Author(s):  
Yazan Numan ◽  
Zaid Abdel Rahman ◽  
Justin Grenet ◽  
Stephanie Boisclair ◽  
Jan Philipp Bewersdorf ◽  
...  
Keyword(s):  
Clinical Activity ◽  
Flt3 Inhibitors ◽  
Previously Treated

CONTACT-01: A phase III, randomized study of atezolizumab plus cabozantinib versus docetaxel in patients with metastatic non-small cell lung cancer (mNSCLC) previously treated with PD-L1/PD-1 inhibitors and platinum-containing chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9134-TPS9134
Author(s):  
Joel W. Neal ◽  
Palak Kundu ◽  
Tomohiro Tanaka ◽  
Ida Enquist ◽  
Sid Patel ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Randomized Study ◽  
Phase Iii ◽  
Clinical Activity ◽  
Open Label ◽  
Eligibility Criteria ◽  
Recist 1.1 ◽  
Platinum Based Chemotherapy ◽  
Patient Reported ◽  
Previously Treated

TPS9134 Background: Patients with mNSCLC who progress on anti–PD-L1/PD-1 therapy administered in combination with or after platinum-based chemotherapy (PBC) are mainly treated with docetaxel or pemetrexed monotherapy. These therapies only have modest clinical activity, leaving a high unmet medical need. Cabozantinib, a tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment and may enhance the efficacy of PD-L1/PD-1 inhibitors, offering a promising second/third-line therapeutic opportunity for patients with mNSCLC. In a Phase Ib multi-cohort study (COSMIC-021; NCT03170960), cabozantinib plus atezolizumab (anti–PD-L1) showed an acceptable safety profile and promising efficacy (ORR: 27%; mDOR: 5.7 mo [range: 2.6-6.9]; disease control rate [CR + PR + SD]: 83%) in 30 patients with mNSCLC who had progressed after prior anti–PD-L1/PD-1 therapy plus chemotherapy (Neal et al. J Clin Oncol 2020). The Phase III CONTACT-01 study will further evaluate the efficacy and safety of atezolizumab plus cabozantinib versus docetaxel monotherapy in patients with mNSCLC who have progressed during or after prior treatment with anti–PD-L1/PD-1 therapy and PBC. Methods: CONTACT-01 (NCT04471428) is a Phase III, multi-center, randomized, open-label study that will enroll ≈350 patients from 150 to 200 sites internationally. Key eligibility criteria include histologically or cytologically confirmed mNSCLC, disease progression with concurrent or sequential anti–PD-L1/PD-1 treatment and PBC, measurable disease (RECIST 1.1), ECOG PS of 0-1 and the availability of tissue specimens for centralized PD-L1 testing or known PD-L1 status using a health authority–approved PD-L1 assay. Patients with NSCLC previously treated with cabozantinib, docetaxel or anti–PD-L1/PD-1 + VEGFR TKIs are excluded. Patients with known sensitizing EGFR/ALK mutations and active or untreated CNS metastases are also excluded. Patients will be randomized 1:1 to receive either atezolizumab (1200 mg IV every 3 weeks) + cabozantinib (40 mg orally once daily) or docetaxel (75 mg/m2 IV every 3 weeks). The primary endpoint is OS. Secondary endpoints include investigator-assessed PFS, ORR and DOR per RECIST 1.1; TTD in patient-reported physical function and global health status (EORTC QLQ-C30); investigator-assessed PFS rates at 6 months and 1 year; OS rates at 1 and 2 years; safety and PK. Clinical trial information: NCT04471428.

A phase 1b multicenter study of trifluridine/tipiracil (FTD/TPI) in combination with irinotecan (IRI) in patients (pts) with metastatic or unresectable gastric and gastroesophageal adenocarcinoma (mGEC) after at least one line of treatment with a fluoropyrimidine and platinum (FP) containing regimen.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16006-e16006
Author(s):  
Farshid Dayyani ◽  
Kit Wah Tam ◽  
Edward Jae-Hoon Kim ◽  
Samuel Ejadi ◽  
Fa Chyi Lee ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Open Label ◽  
Meaningful Improvement ◽  
Best Response ◽  
Previously Treated ◽  
Phase 1B

e16006 Background: FTD/TPI, an antimetabolite, is approved for treatment of refractory mGEC. This study sought to determine whether the combination of FTD/TPI with IRI (“TASIRI”) was safe and effective in mGEC previously treated with FP. Methods: This investigator‐initiated, multicenter, open‐label, single-dose level, single‐arm phase 1b study enrolled pts with mGEC previously treated with at least one line of FP containing regimen. FTD/TPI was given at 25 mg/m2 twice daily on days 1 to 5 with 180 mg/m2 IRI on day 1 of a 14‐day cycle. The primary endpoint was progression-free survival at six months (mo) (PFS-6). The aim was to show an improvement of PFS-6 from 15% to at least 30% based on historical controls. Results: At the time of data-cutoff (03Feb2021), 23 pts were screened and ultimately 20 pts were treated. The study met its primary endpoint. With a median follow-up of 9.8 mo (range 0.7 – 17), 8 pts are still on treatment and 4 pts have died. PFS-6 is 53.9% (lower limit of 95% CI: 28%). Median PFS and overall survival are 6.9 mo and not reached, respectively. At the time of data-cutoff, data were available for 13 pts with measurable disease by RECIST criteria and at least 1 on-treatment scan. Of those, 11 had stable disease and 2 had progressive disease as best response (5 pts had tumor shrinkage < 30%), therefore the disease control rate was 84.6%. The most common any grade (G) treatment related adverse events (TRAE) were nausea (n = 14, 70%), diarrhea (n = 9, 45%), and fatigue (n = 8, 40%). G3-4 TRAE in > 5% of pts were anemia (17%) and neutropenia (9%). 2 serious TRAE were reported: G4 febrile neutropenia (n = 1) and G3 hypotension (n = 1). There was no G5 TRAE. Conclusions: The combination of TASIRI showed encouraging clinical activity with a meaningful improvement in PFS-6 compared to historic controls. TASIRI was well tolerated and no new safety signals were seen. TASIRI warrants further investigation for patients with refractory mGEC and limited treatment options. Updated results with longer follow-up will be presented at the meeting. Clinical trial information: NCT04074343.

Phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors.

1998 ◽  
Vol 16 (12) ◽  
pp. 3858-3865 ◽  
Author(s):  
L B Saltz ◽  
D Spriggs ◽  
L J Schaaf ◽  
G K Schwartz ◽  
D Ilson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Irinotecan Dose ◽  
Pharmacologic Study

PURPOSE In vitro synergy between cisplatin and irinotecan (CPT-11) has been reported. We designed a combination schedule of these agents to maximize the potential for synergistic interaction. PATIENTS AND METHODS To maximize the opportunity for synergy, we divided the cisplatin into four consecutive weekly treatments, followed by a 2-week rest. Each dose of cisplatin was immediately followed by a dose of irinotecan. The dose of cisplatin was fixed at 30 mg/m2/wk. The initial irinotecan dose was 50 mg/m2/wk and this was escalated by 30% increments in successive cohorts of three to six patients to establish the maximum-tolerated dose (MTD). Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were analyzed. RESULTS Of 35 patients with solid tumors enrolled onto this trial, 30 were assessable for toxicity and response. The MTD for this regimen was 30 mg/m2/wk of cisplatin plus 50 mg/m2/wk of irinotecan in previously treated patients and 30 mg/m2/wk of cisplatin plus 65 mg/m2/wk of irinotecan in chemotherapy-naive patients. Neutropenia was the dose-limiting toxicity (DLT) encountered in this trial. Diarrhea was infrequent and rarely dose-limiting. Seven of 30 assessable patients achieved a partial response. No alteration in irinotecan, SN-38, or SN-38G pharmacokinetics resulted from the administration of cisplatin with irinotecan. CONCLUSION The administration of cisplatin and irinotecan on this weekly schedule provides a practical and well-tolerated regimen that has the potential to maximize any clinical synergy between the two agents. Evidence of substantial clinical activity was seen in this phase I study.

scholarly journals Clinical Activity and Safety of Anti-Programmed Death-1 (PD-1) (BMS-936558/MDX-1106/ONO-4538) in Patients (PTS) with Previously Treated, Metastatic Renal Cell Carcinoma (MRCC)

2012 ◽  
Vol 23 ◽  
pp. ix258-ix259 ◽  
Author(s):  
D.F. McDermott ◽  
C.G. Drake ◽  
M. Sznol ◽  
T.K. Choueiri ◽  
J.D. Powderly ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Clinical Activity ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Previously Treated

FLT3 Inhibitor Therapy for Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML): Impact On Survival According to FLT3 Status.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1026-1026 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Borthakur Gautam ◽  
...  
Keyword(s):  
Research Funding ◽  
Initial Therapy ◽  
Inhibitor Therapy ◽  
Clinical Activity ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Flt3 Inhibitor ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Impact On Survival

Abstract Abstract 1026 Poster Board I-48 Background: FLT3 mutations (ITD or D835 point mutation) are frequently observed in patients (pts) with AML and they confer an adverse prognosis, particularly among pts with diploid karyotype. This has made FLT3 an important target for drug development in AML. Several FLT3 inhibitors are currently being developed (eg, sorafenib, PKC-412, AC-220, CEP-701, IMC EB10, sunitinib). Results from early trials with many of these agents suggest they have clinical activity in the treatment of MDS and AML, although most responses are represented by a marked decrease in blast counts, with few complete remissions(CR). Whether these responses ultimately improve long-term outcome of pts, and whether they may be particularly beneficial for pts with FLT3 mutations compared to those with FLT3 wild-type (WT) is being investigated. Aims: To ascertain outcomes of patients given treatment with FLT3 inhibitors, alone or in combination with other therapies, and to compare outcomes in those patients with FLT3 mutations (ITD or D835) versus those with FLT3-WT. Methods: We reviewed the records of patients with MDS and AML who were enrolled on clinical trials with FLT3 inhibitors at our institution. We compared patient outcomes in those who received a FLT3 inhibitor in both FLT3 positive and FLT3 negative patients. Pts were classified as receiving FLT3 inhibitors 1) as part of their initial therapy, 2) as first salvage, or 3) as second salvage or beyond. Results: A total of 128 pts were included: 51 (40%) with FLT3-WT, 56 (44%) with FLT3-ITD, 11 (9%) with D835, and 10 (8%) had both FLT3-ITD and D835. The overall median age was 62 yrs (range, 17-88); by FLT3 status, median age was 70 yrs (35-88) for FLT3-WT pts and 58 yrs (17-81) for FLT3 mutated. Sixty-four pts (50%) were female. Twenty-three (18%) pts received FLT3 inhibitors as part of their induction therapy (18 FLT3-WT, 5 FLT3 mutated; median age 74 yrs); 22 (17%) as first salvage (4 FLT3-WT, 18 mutated; median age 67 yrs); and 83 (65%) as second or later salvage (29 FLT3-WT, 54 mutated; median age 59 yrs). Nine pts overall, all of whom were FLT3 mutated, achieved either CR (n=6) or CRp (n=3) with FLT3 inhibitors. Eight of the nine CR/CRp have been lost with a median CR duration of 8 months (mo) (3-12+). After a median follow-up of 3.5 mo, 115 (90%) pts have died, including 47 (92%) FLT3-WT, and 68 (88%) FLT3 mutated. The median survival is 3.8 mo for the total population. Survival by mutation status and timing of FLT3 inhibitor therapy is presented in table 1. Conclusions: Despite the inferior outcome expected for pts with FLT3 mutations, and the low rate of CR/CRp with FLT3 inhibitors, these results suggest that therapy with FLT3 inhibitors has the potential to improve the outcome of pts with FLT3 mutations. Additional studies incorporating these agents in AML therapy are warranted. Disclosures: Off Label Use: Sorafenib has not been FDA approved for use in MDS and AML. Kantarjian:Novartis: Research Funding. Cortes:Ambit: Research Funding; Novartis: Research Funding; ImClone: Research Funding.

A Multicentre Phase II Study of the Aminopeptidase Inhibitor, CHR- 2797, in the Treatment of Elderly and/or Previously Treated patients with Acute Myeloid Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 961-961 ◽  
Author(s):  
B. Lowenberg ◽  
F. Davies ◽  
C. Müller-Tidow ◽  
Ulrich Dührsen ◽  
A. Burnett ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Single Agent ◽  
Clinical Activity ◽  
Open Label ◽  
Elderly Aml ◽  
Previously Treated Patients ◽  
Previously Treated

Abstract Tosedostat (TSD, CHR-2797) is an aminopeptidase inhibitor that selectively depletes amino acid pools in malignant cells, resulting in anti-proliferative, pro-apoptotic and antiangiogenic effects. In a phase I study, treatment with TSD resulted in complete remission in a number of refractory AML patients. The primary objective of this phase II study was to determine whether TSD was a sufficiently effective therapy to warrant pivotal studies. Methods. This was an open label, single agent, phase II study to assess clinical activity of TSD in elderly and/or previously treated patients with AML/MDS. Patients were treated with once daily oral doses of the maximum acceptable dose (130 mg) of TSD for up to 84 days. Further treatment was allowed if, in the opinion of the investigator, this was considered to be beneficial. Clinical responses were assessed by monthly bone marrow aspirates and weekly hematological assessments. Results. Of the 41 TSD-treated patients with AML (n=38) or MDS (n=3), who were enrolled between March and October 2007, 27 were male, 14 female, with a mean age of 67 years (range 34–82). The median performance status (ECOG) at baseline was 1 (range 0–2). Twelve (31.6%) AML patients and 2 (66.7%) MDS patients were chemotherapy naïve, and 9 (23.7%) AML patients had either secondary disease or adverse cytogenetics. For 16 (39%) patients, treatment with TSD was a second or later salvage attempt. Thirty two patients (30 AML, 2 MDS-RAEB1 and 2) received ≥28 days treatment, and 21 (51.2%) patients completed the formal 84-day study period (19 AML, 2 MDS). Nine (22%) of the patients (7 AML, 2 MDS) continued treatment with TSD after 84 days, and 6 (15%) patients were on TSD in total for more than 6 months (4 AML, 2 MDS). Ten (26.3%) of the AML patients responded to treatment; amongst these, 2 patients received TSD as 2nd/3rd salvage therapy, and a further 2 patients did not show a complete response (CR) after 2 previous induction courses of chemotherapy. Three AML patients achieved a CR (< 5% blasts in bone marrow), of whom 2 were in durable remission (232 days, continuing*; 171 days), and 7 had a partial response (PR, 5–15% blasts) lasting approximately 1–3 months. Two (66.7%) of the MDS patients also responded to treatment with TSD; these patients maintained stable disease for more than 6 months. All responders (CR, PR and SD) were >60 years at the time of the first dose. Median overall survival in AML patients was 130 days (range 8 – 478 days*). The most frequently reported adverse events were: fatigue (61%), thrombocytopenia (49%), pyrexia (39%), peripheral edema (39%) and diarrhea (34%); 9 (22%) patients withdrew due to drug related toxicity. TSD had no effect on hemoglobin or neutrophils. Conclusions. This study in patients with advanced AML/MDS with adverse prognosis demonstrates the anti-leukemic activity of TSD in elderly AML patients, as measured by CR and decreases in leukemic blasts. In addition, 2 relapsed high risk MDS patients achieved disease stabilization. TSD at 130mg qd is also very well tolerated over a long period of exposure (6–10 months). These results support further pivotal studies with TSD in elderly AML and MDS patients.

A Phase I Trial of TGR-1202, a Next Generation Once Daily PI3K-Delta Inhibitor in Combination with Obinutuzumab Plus Chlorambucil, in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2942-2942 ◽  
Author(s):  
Daruka Mahadevan ◽  
Emily K. Pauli ◽  
Kathy Cutter ◽  
Lee Ann Dietz ◽  
Peter Sportelli ◽  
...  
Keyword(s):  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Once Daily ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Btk Inhibitor ◽  
Equity Ownership ◽  
Anti Cd20 ◽  
Ecog Ps

Abstract Introduction: TGR-1202 is a next generation, once daily, oral PI3Kδ inhibitor that displays promising clinical activity in patients with relapsed and refractory hematologic malignancies, with a differentiated safety and tolerability profile compared to other PI3Kδ inhibitors (Burris, ASCO 2015). Obinutuzumab is a glycoengineered Type II anti-CD20 monoclonal antibody approved for patients with chronic lymphocytic leukemia (CLL) in combination with chlorambucil. TGR-1202 has previously been combined with a similarly glycoengineered Type I anti-CD20 mAb, ublituximab, demonstrating clinical activity in patients with heavily pre-treated hematologic malignancies (Lunning, ASCO 2015). The purpose of this study is to explore the safety and efficacy of TGR-1202 + obinutuzumab + chlorambucil in patients with CLL, evaluating a novel treatment regimen of a glycoengineered anti-CD20 with a PI3Kδ inhibitor. Methods: Eligible patients have a diagnosis of CLL/SLL with an ECOG PS ≤ 2. TGR-1202 is escalated in a 3 + 3 design. Cohort 1 was intiated at 800 mg of an initial formulation, with an improved micronized formulation introduced in Cohort 2 at 400 mg and increased in subsequent cohorts. Obinutuzumab is administered as a fixed IV infusion at 1000 mg on days 1, 8 and 15 of cycle 1, followed by day 1 of cycles 2 - 6. Chlorambucil is administered at 0.5 mg/kg on days 1 and 15 of cycle 1 and optional for cycles 2 - 6. After cycle 6, patients remain on TGR-1202 monotherapy until disease progression. Safety is the primary endpoint and is evaluated by CTCAE v. 4.0. Efficacy (ORR and duration of response) is a secondary endpoint, with responses evaluated according to IWCLL (Hallek, et. al. 2008). Results: As of August 2015, 18 patients (15 naïve/3 rel/ref) have been enrolled: Median age is 66 years (range 51-85y); 12 female/6 male, median ECOG PS = 1. FISH from the 3 relapsed patients are del13q/del17p, del11q/del17p and del11q/+12/del13q and 4 treatment naïve patients with 11q del only. All patients are evaluable for safety: AE's have been manageable, with neutropenia (61% Gr3/4), thrombocytopenia (33% Gr3/4) and increases in ALT/AST (28% Gr3/4) being the most frequent Gr3/4 events reported. Chlorambucil was discontinued in 4 patients in cycle 2 due to adverse events. No patient discontinued TGR-1202 due to ALT/AST elevations or neutropenia. 17 patients are evaluable for efficacy of which 14 were treatment naïve and 3 were previously treated, notably all 3 of which had previously progressed on a BTK inhibitor. To date, 93% (13/14) of the treatment naïve patients have achieved an objective response, including 4/14 (28%) complete responses, while 2/3 previously treated patients have achieved a response. The remaining 2 patients not in response have stable disease with 48% and 42% nodal reductions, respectively, with both remaining on study. Notably 6 of the 14 treatment naïve patients (43%) are MRD negative by peripheral blood. Conclusions: The combination of TGR-1202 + obinutuzumab + chlorambucil is well tolerated, with clinical activity observed in all patients, including patients with del17p, previously progressing on a BTK inhibitor. 7/14 (50%) of treatment naïve patients, including those with del11q, achieved either a CR or MRD negativity. Neutropenia, the highest reported AE, was manageable. Notably the ALT/AST increases observed with this combination have not been seen when TGR-1202 is administered as a single agent or in combination with another glycoengineered anti-CD20 mAb, ublituximab (<5% ALT/AST increase; N=137; O'Connor, ICML 2015). Disclosures Mahadevan: Pharmacyclics: Speakers Bureau; Alexion: Speakers Bureau. Pauli:Clearview Cancer Institute: Employment; TG Therapeutics, Inc.: Consultancy, Research Funding. Cutter:Clearview Cancer Center: Employment. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Schreeder:TG Therapeutics, Inc: Research Funding.

Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced melanoma (MEL).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8507-8507 ◽  
Author(s):  
F. Stephen Hodi ◽  
Mario Sznol ◽  
David F. McDermott ◽  
Richard D. Carvajal ◽  
Donald P. Lawrence ◽  
...  
Keyword(s):  
Performance Status ◽  
Tumor Burden ◽  
Clinical Activity ◽  
Ecog Performance Status ◽  
Activated T Cells ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Previously Treated ◽  
Grade 3 ◽  
Dose Levels

8507 Background: BMS-936558 is a fully human mAb that blocks the programmed death-1 (PD-1) co-inhibitory receptor expressed by activated T cells. This study describes the activity and safety of BMS-936558 in patients (pts) with previously treated advanced MEL and underscores the importance of the PD-1/PD-L1 pathway in MEL therapy. Methods: BMS-936558 was administered IV Q2WK to pts with various solid tumors at doses of 0.1 to 10 mg/kg during dose-escalation and/or cohort expansion. Pts received up to 12 cycles (4 doses/cycle) of treatment or until PD or CR. Clinical activity was assessed by RECIST 1.0. Results: Of 240 pts treated as of July 1, 2011, 95 MEL pts were treated with BMS-936558 at 0.1 (n=13), 0.3 (n=17), 1 (n=28), 3 (n=17), or 10 mg/kg (n=20). ECOG performance status was 0/1/2 in 56/36/3 pts. The majority of pts (60/95) had received prior immunotherapy (IT), primarily interferon-alpha or IL-2 (prior anti-CTLA-4 excluded). Prior B-raf inhibitor therapy was noted in 7/95 pts. The number of prior therapies was 1 (n=35), 2 (n=34), or ≥3 (n=26). Sites of metastatic disease included lymph node (n=60), liver (n=32), lung (n=55), and bone (n=10). Median duration of therapy was 15 wk (max 120 wk), with 40 pts still receiving treatment. The incidence of grade 3-4 related AEs was 19% and included gastrointestinal (4%), endocrine (2%), and hepatobiliary disorders (1%). There were no drug-related deaths in MEL pts. Clinical activity was observed at all dose levels (Table). Of 20 pts with OR at the time of data lock, 12 had OR duration ≥1 yr and 6 pts were on study with OR duration between 1.9 and 11.3 mo. OR were seen in pts with visceral or bone metastases. Several pts had prolonged SD. Some had a persistent decrease in overall tumor burden in the presence of new lesions and were not categorized as responders. Conclusions: BMS-936558 had durable clinical benefit in pts with advanced MEL, including those who had received prior IT. Further development of BMS-936558 in MEL is ongoing. [Table: see text]

Activity of a novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients previously treated with anti-PD1 blockade therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3014-3014 ◽  
Author(s):  
Brendan D. Curti ◽  
Jon M. Richards ◽  
Sigrun Hallmeyer ◽  
Mark B. Faries ◽  
Robert Hans Ingemar Andtbacka ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Cell ◽  
Phase 1 ◽  
Unmet Need ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Potential Marker ◽  
Previously Treated ◽  
Coxsackievirus A21 ◽  
Melanoma Patients

3014 Background: CAVATAK is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21 (CVA21) that when injected into melanoma lesions can increase immune-cell infiltration, up-regulation of γ-INF response and immune-checkpoint genes, including CD122, which may be a potential marker for enhanced anti-tumor activity by anti-CTLA-4 blockade. Intratumoral replication of CVA21 may act as a strong “immune-sequestration signal” to circulating activated T-cells following CTLA-4 blockade. A large unmet need exists for active therapies in melanoma patients (pts) following treatment (tx) with anti-PD1 therapies. We present in a Phase 1 study, the clinical activity of a CVA21/ ipilimumab (ipi) combination following anti–PD1 therapy in advanced melanoma pts. Methods: The Phase Ib MITCI study (NCT02307149) investigated the efficacy and safety of i.t. CVA21 and i.v. ipi in 26 pts with unresectable Stage IIIB/C-IVM1c melanoma with 13 pts previously treated with anti-PD1 therapies. Pts received up to 3 x 108 TCID50CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then q3w for a further 6 series of injections. Ipi (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. Results: Analysis of the prior anti–PD1 treated pts (n=13) revealed that the combination tx was generally well-tolerated with one case of Gr 3 ipi-related liver toxicity observed. Of the tx population, 54% (7/13) had received prior ipi tx in addition to anti-PD1, 85% (11/13) of pts were stage IV M1b/c, with the median time between the last anti-PD1 and first CVA21 and ipi doses being 5.7 and 8.7 weeks, respectively. The mean number of prior systemic therapies including anti-PD1 tx was 2.6. For all pts completing at least the first investigator response assessment (irWHO criteria at Day 106) we observed a confirmed BORR of 38.0% (3/8) and a DCR (CR+PR+SD) of 88% (7/8). Conclusions: Intratumoral CVA21 + ipilimumab treatment in anti–PD1 treated pts has displayed promising clinical activity together with low adverse toxicity and as such this regimen may represent a valuable tx option for pts that have been administered previous lines of immune checkpoint therapy. Clinical trial information: NCT02307149.

Staccato pulse interleukin-2 (IL-2) in metastatic melanoma (MM) previously treated with checkpoint inhibitors (CPI).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e21022-e21022
Author(s):  
Walter Quan ◽  
Leah I Gutierrez ◽  
Kyle Quan ◽  
Francine Marie Quan
Keyword(s):  
Soft Tissue ◽  
Lymph Nodes ◽  
Checkpoint Inhibitors ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Clinical Activity ◽  
Common Disease ◽  
Outpatient Basis ◽  
Previously Treated ◽  
Lung Lymph

e21022 Background: The CPI ipilimumab, nivolumab, and pembrolizumab have been adopted into common use for patients (pts) with MM. While their clinical activity is undeniable, a substantial fraction of pts treated with these agents experience disease progression. Additional approaches are therefore needed. Intravenous IL-2 given via daily single intravenous infusions (pulses) has been developed to mitigate toxicity while maintaining anticancer activity against MM. Staccato pulse IL-2 is based on three prior observations. Daily IL-2 schedules have previously been demonstrated to induce Lymphokine Activated Killer cell (LAK) activity [Mitchell, 1989]. LAK generated by IL-2 then subsequently exposed to more IL-2 display enhanced cytotoxicity in vitro [Hank, 1990]. Increased numbers of LAK are seen in pts with melanoma treated with daily IL-2 [Quan, 2011]. Methods: In this retrospective study, ten pts with MM were treated with IL-2 18 Million IU/M2 intravenously over 15-30 minutes on days 1-3 and 21.6 Million IU/M2 intravenously over 15-30 minutes on day 5 on an outpatient basis. Cycles were repeated every 3 weeks. Results: Characteristics: 8 females/ 2 males, median age-56 (range: 21-74), median ECOG-1 (0-1); common disease sites: lymph nodes (12), subcutaneous (6), lungs (5), soft tissue (4). Prior CPI: Ipilimumab (8); Pembrolizumab (5); Nivolumab (2). Common toxicities: nausea/emesis (8), myalgia/arthralgia (5), sinus/catarrhal symptoms (5), fatigue (5), and hypotension requiring intravenous fluids (5). No pts required hospitalization for toxicity related to therapy. Median number of cycles: 3 (2-8). Four pts have had partial responses (total response rate = 40%; 95% CI: 10-70%). The median duration of response exceeds 7.4+ months. One pt having had resolution of prior lung, lymph node, and peritoneal metastases (partial response of 24.5+ months) underwent surgical resection of the residual intraabdominal disease focus and is free of disease at 36.5+ months. Overall, responses have occurred in lung, lymph nodes, subcutaneous, bones, peritoneum, small bowel, and soft tissue sites. Conclusions: Staccato pulse intravenous IL-2 has activity in melanoma pts previously treated with CPI.

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