Safety and efficacy of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) and/or FOLFOX in patients (pts) with metastatic colorectal cancer (mCRC).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 704-704 ◽  
Author(s):  
Johanna C. Bendell ◽  
John D. Powderly ◽  
Christopher Hanyoung Lieu ◽  
S. Gail Eckhardt ◽  
Herbert Hurwitz ◽  
...  
Keyword(s):  
Single Agent ◽  
Clinical Activity ◽  
Open Label ◽  
Activated T Cells ◽  
Safety And Efficacy ◽  
Cell Immunity ◽  
Liver Biopsies ◽  
Prior Systemic Therapy ◽  
Grade 3

704 Background: Cancers can mediate immune evasion via upregulation of PD-L1; blocking PD-L1 may restore tumor-specific T-cell immunity. MPDL3280A, a human anti-PD-L1 mAb containing an engineered Fc domain, prevents PD-L1 binding to its receptors PD-1 and B7.1 on activated T cells. Single-agent MPDL3280A has shown clinical activity in various indications, including NSCLC, bladder cancer, RCC and CRC. VEGF blockade has shown immunomodulatory properties, and certain chemotherapies may have immunogenic effects. Therefore we examined the safety and efficacy of MPDL3280A + bev with or without FOLFOX. Methods: MPDL3280A + bev in refractory mCRC pts (Arm A) and MPDL3280A + bev + FOLFOX in oxaliplatin-naive mCRC pts (Arm B) were evaluated in an open-label, multicenter Phase Ib study. Arm A pts received MPDL3280A 20 mg/kg q3w and bev 15 mg/kg q3w. Arm B pts received MPDL3280A 14 mg/kg q2w, bev 10 mg/kg q2w and mFOLFOX6 at standard doses. Responses were assessed by RECIST v1.1. Potential biomarkers were assessed in pre- and on-treatment liver biopsies. The clinical data cutoff was July 7, 2014. Results: 14 mCRC pts in Arm A and 30 in Arm B were evaluable for safety. In Arm A, median age was 56 y, 29% were male and all had ≥3 prior systemic regimens. In Arm B, median age was 57 y, 53% were male and 70% had no prior systemic therapy. In Arm A, grade 3-4 AEs regardless of attribution were 64%, including abdominal pain, hyperbilirubinemia and pneumonia (14% each). 73% of Arm B pts had grade 3-4 AEs, including neutropenia (40%), diarrhea (13%), increased ALT (10%) and increased AST (10%). Grade ≥3 MPDL3280A-related AEs were 7% in Arm A and 20% in Arm B. For pts with ≥1 tumor assessment, the unconfirmed ORR was 8% (1/13) in Arm A and 36% (9/25) in Arm B. The unconfirmed ORR was 44% (8/18) for Arm B first-line pts. Minimum follow-up was 1.9 mo in Arm A and 2.2 mo in Arm B. Updated data, including biomarkers, will be presented. Conclusions: MPDL3280A + bev with or without FOLFOXwas well tolerated with no unexpected toxicities. Clinical activity was observed with both treatment combinations. Longer follow-up and randomized studies will be needed to estimate the potential benefit of adding MPDL3280A to chemotherapy. Clinical trial information: NCT01633970.

Inducible T-cell co-stimulatory (ICOS) receptor agonist, feladilimab (fela), alone and in combination (combo) with pembrolizumab (P): Results from INDUCE-1 urothelial carcinoma (UC) expansion cohorts (ECs).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4519-4519
Author(s):  
Arjun Vasant Balar ◽  
Victor Moreno ◽  
Eric Angevin ◽  
Hui Kong Gan ◽  
Maria Vieito ◽  
...  
Keyword(s):  
T Cell ◽  
Single Agent ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Metastatic Setting ◽  
Duration Of Response ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Tumor Types

4519 Background: INDUCE-1 is a first-in-human trial evaluating fela, an IgG4 ICOS agonist non-T-cell depleting mAb, as monotherapy (mono) and in combo with P. ECs include tumor types, such as UC, with high ICOS expression and immunotherapy-favorable features. Fela induced IFNγ, increased PD-1/L1 expression, and enhanced antitumor activity in combo with PD-1 blockade nonclinically. We report preliminary efficacy, safety, and biomarker data of fela ± P in INDUCE-1 UC ECs. Methods: Eligible patients (pts) had recurrent/metastatic (R/M) UC of the upper or lower urinary tract, ≤6 prior systemic therapy lines in the advanced setting, measurable disease, and no active autoimmune disease. Pts received 0.3 or 1 mg/kg fela (mono EC; anti-PD-1/L1–experienced [exp] pts) or 0.3 mg/kg fela + 200 mg P (combo EC; anti-PD-1/L1–naïve pts) every 3 wks, up to 35 cycles until disease progression or unacceptable toxicity. Disease was assessed every 9 wks through wk 54, then every 12 wks. Archival and/or fresh biopsy tumor tissue was collected for biomarker analyses and safety assessed. Results: By Nov 6 2020, 13 anti-PD-1/L1–exp and 32 anti-PD-1/L1–naïve pts were evaluable in the mono and combo ECs, respectively. In the mono EC, median age was 69 yrs (range: 47–82), 92% of pts were male, and 85% received ≥2 prior therapy lines in the metastatic setting. In the combo EC, median age was 70 yrs (range: 42–84), 75% of pts were male, and 72% received ≥1 prior therapy line in the metastatic setting. In the mono EC, median duration of follow-up (mDoF) was 10.6 mo (range: 1.1–22.8); overall response rate (ORR) was 8% (1 partial response [PR]; 95% CI: 0.2, 36.0) with a duration of response (DoR) of 6.1 mo; disease control rate (DCR [response or stable disease for ≥9 wks]) was 23% (95% CI: 5.0, 53.8), and median overall survival (mOS) was 14.5 mo (95% CI: 2.8, NR), with 74% of pts alive at 6 mo. In the combo EC, mDoF was 9.6 mo (range: 0.9–28.3); ORR was 22% (7 PRs; 95% CI: 9.3, 40.0) with a median DoR of 8.3 months (range: 3.5–23.3+); DCR was 63% (95% CI: 43.7, 78.9), and mOS was 10.7 mo (95% CI: 5.2, 18.1), with 64% of pts alive at 6 mo. Grade ≥3 treatment-related AEs were reported for 0% and 9% of pts in the mono (N = 16) and combo (N = 44) safety populations, respectively. PD-L1 expression and ICOS-specific biomarkers are being evaluated, with promising trends observed in enrichment of clinical activity in preliminary analyses. Conclusions: Fela is the first ICOS agonist with reported single-agent activity in anti-PD-1/L1–exp relapsed/refractory UC. Fela + P in combo shows promising clinical activity and manageable safety in PD-1/L1–naïve R/M UC. Further study is warranted. Updated data to be presented. Funding: Study 204691 (NCT02723955) funded by GlaxoSmithKline in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. Clinical trial information: NCT02723955.

Randomized phase II trial of sorafenib, capecitabine and oxaliplatin (SECOX) versus single agent sorafenib in patients with advanced hepatocellular carcinoma.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 365-365
Author(s):  
Thomas Cheung Yau ◽  
Vikki Tang ◽  
Roland Ching-Yu Leung ◽  
Gin Wai Kwok ◽  
Ann-Shing Lee ◽  
...  
Keyword(s):  
Single Agent ◽  
Hepatocellular Cancer ◽  
Progression Free Survival ◽  
Advanced Hepatocellular Carcinoma ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Common Grade ◽  
Secondary Endpoints ◽  
Prior Systemic Therapy ◽  
Grade 3

365 Background: We aimed to compare the efficacy and tolerability of SECOX regimen with sorafenib alone as first-line treatment of advanced hepatocellular cancer (HCC) in a multicenter, open-label and randomized setting. Methods: Patients not suitable for surgery or various loco-regional therapies and no prior systemic therapy for advanced HCC were recruited in 3 centres. Eligible patients were randomly assigned to receive either SECOX (sorafenib 400 mg BD continuously, oxaliplatin 85 mg/m2 on D1, and capecitabine 1700 mg/m2 on D1-7 q2w) or sorafenib alone continuously in 1:1 ratio. Primary endpoint was time-to-progression (TTP). Secondary endpoints were tolerability, overall tumor response rate, overall survival (OS) and progression-free survival (PFS). Results: Forty-six patients were randomized and treated, of whom 22 were in the SECOX arm. Median age was 64 years and majority of the patients were male (72%). 40 patients (87%) were hepatitis B carrier, and 42 patients (91%) had Child-Pugh A liver function. Thirty patients (65%) had received prior non-systemic treatment for HCC. Median duration of follow-up was 7.8 months (mos) (range 0.3-25.8). At the time of analysis,one patient in the SECOX arm is still receiving treatment. Median TTP was 3.2 mos (95% CI 1.7-5.8) for SECOX vs 2.8 mos (95% CI 1.8-4.0) for sorafenib. The hazard ratio (HR) for TTP was 0.91 (95% CI 0.5-1.7; p=0.77; predetermined futility boundary HR ≥ 0.86). Median OS was 7.1 mos (95% CI 3.0-15.3) for SECOX vs 12.5 mos (95% CI 7.2-15.4) for sorafenib (p=0.29). Median PFS was 3.1 mos (95% CI 1.6-5.8) for SECOX vs 2.7 mos (95% CI 1.8-4.0) for sorafenib. 2 patients (9%) and no patients achieved partial response in the SECOX and sorafenib arms, respectively. The clinical benefit rate (CR+PR+SD) was 36% for the SECOX arm and 21% for the sorafenib arm (p=0.50). Incidence of treatment-related adverse events (trAEs) was common in both SECOX and sorafenib arms (64% and 71% respectively, p=0.75). The most common grade 3-4 trAE was ALP increase (14%) for SECOX and hand-foot skin reaction (25%) for sorafenib. Conclusions: The addition of capecitabine and oxaliplatin to sorafenib did not result in significant improvement in TTP. Clinical trial information: NCT02716766.

Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory lymphoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8518-8518 ◽  
Author(s):  
Steven M. Horwitz ◽  
Ian Flinn ◽  
Manish R. Patel ◽  
Anas Younes ◽  
Francine M. Foss ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Early Results ◽  
Refractory Lymphoma ◽  
Grade 3

8518 Background: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. IPI-145, a potent oral inhibitor of the PI3KEδ and PI3K-γ isoforms, is in clinical development for patients (pts) with hematologic malignancies. Early results in pts with relapsed/refractory lymphoma from an ongoing Phase 1 study are reported here. Methods: This dose-escalation study evaluates the safety, maximum tolerated dose (MTD), clinical activity, and pharmacokinetics (PK) of IPI-145. Expansion cohorts (EC) < MTD are allowed. IPI-145 is given orally twice daily (BID) in 28-day cycles. Tumor response is based on standard disease-specific criteria. Results: 55 pts have been dosed with IPI-145. PK, available through 50 mg BID, are linear with complete inhibition of PI3K-δ at doses > 15 mg BID and increasing suppression of PI3K-γ with increasing dose. In the 36 pts with lymphoma who received 15 mg to 75 mg BID, the median [range] number of cycles was 2.4 [0.1–10] and 67% remain on study. Treatment-related adverse events (TRAEs) occurred in 50% of pts with lymphoma. Neutropenia and increased ALT were the most common ≥ Grade 3 TRAEs (4 pts each) and were not associated with increasing dose. > Grade 3 ALT elevations were more common in lymphoma pts (18%) compared to non-lymphoma pts (5%). Among evaluable pts with lymphoma (n=27), early clinical activity was observed in T-cell (n=6, 1 CR, 1 PR, 1 SD) and aggressive/indolent B-cell (n=21, 2 CR, 9 PR, 5 SD) lymphoma pts at ≤ 75 mg BID. 92% of responses were observed by 3 months. Conclusions: IPI-145 appeared well tolerated and has shown clinical activity in pts with relapsed/refractory advanced B- and T-cell lymphoma across the range of doses examined. The single agent MTD has not been determined and dose escalation continues. Updated safety and efficacy data from pts with lymphoma enrolled in dose escalation or ECs evaluating 25 mg BID and a higher dose (< MTD) of IPI-145 will be presented. Clinical trial information: NCT01476657.

First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): Results from a phase Ib trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4504-4504 ◽  
Author(s):  
Toni K. Choueiri ◽  
James M. G. Larkin ◽  
Mototsugu Oya ◽  
Fiona C. Thistlethwaite ◽  
Marcella Martignoni ◽  
...  
Keyword(s):  
Objective Response ◽  
Clinical Activity ◽  
Vegf Receptor ◽  
Phase Ib ◽  
Treatment Naïve ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Ecog Ps ◽  
Tumor Types

4504 Background: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for treatment of aRCC. Avelumab is a fully human anti–PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib, a VEGF receptor inhibitor, is approved for second-line treatment of aRCC. JAVELIN Renal 100 (NCT02493751) is a phase Ib study evaluating safety and clinical activity of avelumab + axitinib in treatment-naïve pts with aRCC; updated results are reported here. Methods: Eligible pts had confirmed clear-cell aRCC, ≥1 measurable lesion, fresh or archival tumor specimen, ECOG PS ≤1, and no prior systemic therapy. Pts received avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID until progression, unacceptable toxicity, or withdrawal. Endpoints included safety (NCI CTCAE v4.03) and objective response (RECIST v1.1). Results: As of Dec 30, 2016, 55 pts (median age 60.0 yrs [range 42.0–76.0]; 76.4% male; 34.5% ECOG PS = 1) were enrolled. 54 pts were treated with avelumab for a median of 24.1 wks (range 2.0–62.0); 55 pts were treated with axitinib for a median of 25.3 wks (range 3.0-61.0). 51 pts (92.7%) had an avelumab-related adverse event (AE) with the therapy combination, the most common (≥30% any grade) were fatigue and diarrhea (30.9% each). 10 pts (18.2%) had a max grade 3 and 1 pt (1.8%) had a max grade 4 avelumab-related AE. 52 pts (94.5%) had an axitinib-related AE with the therapy combination; the most common (≥30% any grade) were diarrhea (52.7%), hypertension (45.5%), dysphonia (43.6%), and fatigue (43.6%). 24 pts (43.6%) had a max grade 3 and 5 pts (9.1%) had a max grade 4 axitinib-related AE. 2 deaths occurred in the study during the reporting period: 1 due to progression and 1 related to both treatments (myocarditis). An AE led to discontinuation of avelumab in 5 pts (9.1%) and axitinib in 4 pts (7.3%). Confirmed ORR was 54.5% (95% CI 40.6–68.0) based on 2 CR and 28 PR. Unconfirmed ORR was 60.0% (95% CI 45.9–73.0). Conclusions: The safety profile of the combination of avelumab + axitinib appears manageable and consistent with those agents administered as monotherapy, and early encouraging antitumor activity was observed. Follow-up is ongoing. Clinical trial information: NCT02493751.

Alpelisib (ALP) + endocrine therapy (ET) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor-2-negative (HER2-) advanced breast cancer (ABC): First interim BYLieve study results.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1040-1040 ◽  
Author(s):  
Hope S. Rugo ◽  
Manuel Ruiz Borrego ◽  
Stephen K. L. Chia ◽  
Dejan Juric ◽  
Nicholas C. Turner ◽  
...  
Keyword(s):  
Pik3ca Mutation ◽  
Safety Data ◽  
Dose Intensity ◽  
Open Label ◽  
Safety And Efficacy ◽  
Hormone Receptor Positive ◽  
Study Results ◽  
Common Grade ◽  
Grade 3

1040 Background: In the phase 3 SOLAR-1 study, ALP + fulvestrant (FUL) improved PFS in pts with HR+, HER2– ABC with a PIK3CA mutation overall and in the small group of pts with prior cyclin-dependent kinase 4/6 inhibitor (CDKi) use. We report interim data from the BYLieve study in pts with PIK3CA-mutated ABC and prior CDKi exposure. Methods: BYLieve is an ongoing, phase 2, open-label, non-comparative study of ALP 300 mg QD + ET in men and women with PIK3CA-mutated HR+, HER2– ABC whose disease progressed on/after CDKi + ET. Pts are permitted ≤2 prior anticancer therapies and ≤1 prior chemotherapy regimen for ABC. Pts with prior CDKi and AI ( FUL cohort) receive ALP and FUL 500 mg Q28d + C1d15 IM. Pts with prior CDKi and FUL ( LET cohort) receive ALP and letrozole (LET) 2.5 mg PO QD. In this preplanned interim analysis, conducted after ≥20 pts in FUL had ≥6 mo of follow-up, descriptive data are reported for preliminary safety and efficacy in the FUL and LET cohorts. Results: At data cutoff, 64 and 36 pts were enrolled in the FUL and LET cohorts, respectively; 39 pts ( FUL, n = 21; LET, n = 18) have safety and efficacy data with ≥6 mo follow-up and are reported here. Data on 100 pts enrolled at the time of data cutoff will be presented. In the 39 pts with ≥6 mo follow-up, median ALP duration was 5.3 and 5.5 mo in FUL and LET, respectively; median duration of FUL and LET was 5.6 mo. Median relative ALP dose intensity was 93% ( FUL) and 87% ( LET). Most common grade ≥3 adverse events were hyperglycemia (38.1% ( FUL) and 27.8% ( LET)) and rash (4.8% ( FUL) and 27.8% ( LET)). Only 2 pts (5%; 1 pt per cohort) discontinued due to an AE. In pts with centrally confirmed PIK3CA mutation (n = 20 ( FUL); n = 17 ( LET)), ORR was 20% ( FUL) and 18% ( LET), CBR was 40% ( FUL) and 35% ( LET). Efficacy and safety data for the 100 enrolled pts will be presented at the meeting. Conclusions: Pending further readout of the ongoing BYLieve trial, safety and tolerability of ALP and hormonal therapy in pts with prior CDKi are consistent with those of SOLAR-1; discontinuation due to toxicity was rare. NCT03056755. Clinical trial information: NCT02437318.

Nilotinib Therapy after Dasatinib Failure in Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP), Accelerated Phase (AP) or Blast Crisis (BC).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1029-1029 ◽  
Author(s):  
Francis J. Giles ◽  
Philipp le Coutre ◽  
Kapil N. Bhalla ◽  
Gert Ossenkoppele ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Clinical Activity ◽  
Open Label ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Background: Nilotinib and dasatinib are the next generation of tyrosine kinase inhibitors (TKIs) which have been developed for use in the treatment of imatinib-resistant/intolerant CML. Few therapeutic options are available for patients (pts) with CML who fail to benefit from or to tolerate first, imatinib, and then, a second generation TKI such as dasatinib and nilotinib. This phase II open-label study was designed to evaluate the safety and efficacy of nilotinib in such pts who either failed or were intolerant to imatinib and dasatinib. Methods: Nilotinib was administered at a dose of 400 mg twice daily (BID) to pts with CML-CP, -AP, and -BC who previously received and either failed or were intolerant to imatinib and dasatinib. Pts who had inadequate hematologic and/or cytogenetic responses at 28 days or who had disease progression could be escalated to 600 mg BID in the absence of safety concerns. Results: A total of 67 evaluable pts are reported with CML-CP (27), -AP (15), and -BC (25 total; 15 myeloid, 8 lymphoid). Overall, 25% of pts had extramedullary disease at baseline (14 spleen, 6 liver). For all pts, median time from first diagnosis was 20 (<1–266) months. The median duration of nilotinib exposure was 85 (2–542) days with median dose intensity of 800 (211–1093) mg/day. A total of 22 (33%) pts with dasatinib failure remained on nilotinib and 45 (67%) discontinued (8 for adverse events, 27 for disease progression). Of 17 pts with CML-CP who did not have a complete hematologic response (CHR) at baseline, 11 (65%) achieved a CHR at 4-month follow-up. Of all 22 pts with CML-CP at 4-month follow-up, 7 (32%) had a major cytogenetic response (3 complete, 4 partial). Disease progression occurred in only 2 pts with CML-CP, both of whom had CHR at baseline. Of 13 evaluable pts with CML-AP, 3 (23%) demonstrated no evidence of leukemia and 3 (23%) had a return to chronic phase (RTC) after 4 months of nilotinib therapy. No pts with CML-AP had disease progression at 4 months. Of 20 evaluable pts with CML-BC, 3 (15%) achieved CHR, 1 (5%) had RTC, and 6 (30%) had disease progression. For all pts (N=67), the most common grade 3/4 hematologic adverse events reported were neutropenia (51%), thrombocytopenia (44%), and anemia (21%). The most frequent grade 3/4 nonhematologic adverse events reported were pyrexia (8%), anorexia and headache (3%), and diarrhea, asthenia, constipation, fatigue, and myalgia (2% each). 3 pts had pleural effusion and 1 had pericardial effusion during nilotinib therapy. Conclusion: Nilotinib has impressive clinical activity in these heavily pretreated pts with CML-CP, -AP, or -BC in whom both imatinib and dasatinib have failed. In addition, nilotinib tolerability and safety profile in this subset of pts was similar to that reported for pts who failed only imatinib.

A randomized phase II study (VEG108838) of lapatanib plus pazopanib (L+P) versus lapatanib (L) in patients with ErbB2+ inflammatory breast cancer (IBC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 531-531 ◽  
Author(s):  
Massimo Cristofanilli ◽  
Stephen R. D. Johnston ◽  
Alexey Manikhas ◽  
Henry Leonidas Gomez ◽  
Oleg Gladkov ◽  
...  
Keyword(s):  
Randomized Study ◽  
Single Agent ◽  
Clinical Activity ◽  
Study Cohort ◽  
Open Label ◽  
Double Blind ◽  
Meaningful Improvement ◽  
Grade 3 ◽  
To Receive ◽  
Dose Reductions

531 Background: ErbB2 amplification is frequently reported in IBC and there is evidence of positive association between ErbB2 and VEGF expression. We evaluated the combination of anti ErbB2 and VEGF therapy in ErbB2+ IBC. Methods: We conducted a multicenter, randomized clinical trial for patients (pts) with relapsed ErbB2+ IBC. Cohort 1: Pts stratified (prior trastuzumab; cutaneous disease only vs systemic) and randomized 1:1 to receive L 1500 mg + placebo or L 1500 mg + P 800 mg, QD. Due to high incidence of Grade 3/4 diarrhea in pts treated with L 1500 mg+ P 800 mg in another study, Cohort 1 was closed after 76 pts randomized. Cohort 2 (87 pts ): Pts were stratified (prior trastuzumab) and randomized 5:5:2 to receive L 1500 mg + placebo or L 1000 mg + P 400 mg (double-blind) or P 800 mg (open-label), respectively, QD. Treatment continued until PD, unacceptable toxicity or death. Primary endpoint was ORR. Secondary endpoints included PFS, OS, and safety. Results: Cohort 1: 76 pts were randomized and treated: L, n=38; L+P, n=38. ORR was 29% for the L arm, and 45% for the L+P arm. Median PFS was 16.1 and 14.3 wks, respectively, for the L and L+P arms. The most frequent Grade ≥3 AEs were diarrhea (0% vs 18%) vomiting (0% vs 8%), ALT increased (0% vs 8%), neutropenia (3% vs 13%), and bilirubin increased (0% vs 5%). Dose reductions due to AE were 3% and 21% and dose interruptions due to AE were 11% and 55% in the L and L+P arms, respectively. Cohort 2: 88 pts were randomized (87 treated): L, n=36; P, n=14; L+P, n=38. The ORR was 47%, 31%, and 58% for the L, P, and L+P arms, respectively. Median PFS was 16.0, 11.4, and 16.0 wks for the L, P, and L+P arms, respectively. The most frequent Grade ≥3 AEs were ALT increased (0%, 0%, 21%), AST increased (0%, 0%, 18%), diarrhea (3%, 8%, 8%), and fatigue (3%, 8%, 8%). Dose reductions due to AE occurred in 0%, 0%, and 13% of pts and dose interruptions due to AE occurred in 22%, 23%, and 39% of pts in the L, P, and L+P arms, respectively. Conclusions: This prospective, randomized study confirmed the clinical activity of lapatinib single agent in metastatic ErbB2+ IBC. Furthermore, we demonstrated increased toxicity associated with the combination without a clinically meaningful improvement in efficacy.

Phase Ib evaluation of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) in patients (pts) with metastatic renal cell carcinoma (mRCC).

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 410-410 ◽  
Author(s):  
Mario Sznol ◽  
David F. McDermott ◽  
Suzanne Fields Jones ◽  
James Walter Mier ◽  
Daniel Waterkamp ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Immune Modulation ◽  
Clear Cell ◽  
Single Agent ◽  
Clinical Activity ◽  
Antitumor Effects ◽  
Activated T Cells ◽  
Phase Ib ◽  
Grade 3

410 Background: MPDL3280A, a human anti-PD-L1 IgG1 mAb engineered to remove Fc-effector function, prevents PD-L1 binding to the inhibitory receptors PD-1 and B7.1 on activated T cells. Single-agent MPDL3280A has demonstrated clinical activity in various cancers, including RCC. Bev was postulated to enhance the antitumor effects of MPDL3280A by blocking VEGF-related suppressive effects on immune function and lymphocyte traffic. Therefore, a multicenter Phase Ib study was conducted to determine the safety and activity of MPDL3280A + bev, including in a cohort of mRCC pts. Methods: mRCC pts with clear cell histology and available pre-treatment tumor specimens were enrolled. In addition to the safety and activity endpoints, an exploratory objective was to assess treatment effects on the tumor microenvironment and peripheral biomarkers. Bev 15 mg/kg was given alone on Cycle 1 Day 1 and concurrently with MPDL3280A 20 mg/kg q3w thereafter. On-treatment tumor biopsy was performed during Cycle 1 and 4-6 weeks after the start of Cycle 2. Objective responses were assessed by RECIST v1.1. The clinical data cutoff was July 7, 2014. Results: 12 pts were evaluable for safety. The median age was 64 y, 58% were male and 83% had no prior systemic therapy. The median duration of exposure was 232.5 days. Grade 3-4 AEs included postoperative wound infection, hypercalcemia, tumor pain, acute respiratory failure in a patient with influenza (1 pt each) and hypertension (3 pts). No Grade 3-4 AEs were assessed as related to MPDL3280A. Among first-line mRCC pts with ≥ 1 tumor assessment (n = 10), the ORR was 40% (3 of 4 responses confirmed at the time of the data cutoff). Minimum follow-up was 2.1 mo. Increases in tumor-infiltrating CD8+ T cells were observed on-treatment. Updated data, including biomarkers, will be presented. Conclusions: The combination of MPDL3280A + bev waswell tolerated in clear cell mRCC pts. Promising preliminary clinical activity and immune modulation of the tumor microenvironment were observed. A Phase II trial of MPLD3280A ± bevacizumab vs sunitinib in pts with previously untreated mRCC is currently ongoing. Clinical trial information: NCT01633970.

GLIAVAX: A stratified phase II clinical trial of avelumab and axitinib in patients with recurrent glioblastoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2034-2034 ◽  
Author(s):  
Bart Neyns ◽  
Laila Ben Salama ◽  
Gil Awada ◽  
Jennifer De Cremer ◽  
Julia Katharina Schwarze ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Agent ◽  
Recurrent Glioblastoma ◽  
Clinical Activity ◽  
Open Label ◽  
Grade 5 ◽  
Phase 2 Clinical Trial ◽  
Prior Surgery ◽  
Grade 3 ◽  
Tumor Types

2034 Background: Patients (pts) with recurrent glioblastoma (rGB) have a poor prognosis, and no treatment option demonstrated to improve survival in a randomized trial. Axitinib (AXI), an oral VEGFR 1-3 inhibitor has demonstrated single agent activity in rGB and reduces the need for corticosteroids (CS). Avelumab (AVE) is a fully human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types. Combination of AXI and AVE may improve the outcome of pts with rGB. Methods: This open-label, dual-strata, single-center phase 2 clinical trial investigated the activity of AXI plus AVE in adult pts with rGB following prior surgery, RT and temozolomide. Pts were stratified according to their baseline use of CS. Pts without baseline need for CS initiated treatment with AXI (5 mg oral BID) plus AVE (10 mg/kg IV Q2W) (cohort-1). Pts in need of CS initiated AXI as a monotherapy; AVE could be added to AXI after 6 wks if the CS dose could be tapered to a physiologic dose level or less (cohort-2). Six-month-PFS served as the primary endpoint (with a prespecified threshold of ≥ 50% for cohort-1) according to Fleming one-stage design. Results: Between Jun 2017 and Aug 2018, 54 pts (27 per cohort) were enrolled (med age 55 y [range 19-75]; 63% male; 91% WHO PS 0-1). All pts in cohort-1 and 16 pts (59%) in cohort-2 received at least 1 dose of AVE. The 6-month-PFS was 18% (95% CI 4-33) in both cohorts. At the time of analysis, 2 pts were progression-free and continuing study treatment. Median OS in cohort-1 and -2 was respectively 26 wks (95% CI 21-32) and 18 wks (95% CI 14-22). No clear relation was found between baseline cognitive functioning (Cogstate subtests) and PFS/OS. The best overall response rate (iRANO) was 41% and 26% respectively for pts in cohort-1 and -2. The most frequent all-grade treatment-related adverse events (TRAE) were dysphonia (67%), lymphopenia (50%), diarrhea (48%), hypertension (48%), and fatigue (46%). The incidence of grade 3-4 TRAE was 30%; there were no grade 5 AE. Conclusions: The combination of AVE plus AXI is sufficiently well tolerated but did not meet the threshold for activity justifying further investigation in an unselected population of patients with rGB. Clinical trial information: NCT03291314.

First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): Updated results for KEYNOTE-427 cohort A.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4570-4570 ◽  
Author(s):  
Scott S. Tykodi ◽  
Frede Donskov ◽  
Jae-Lyun Lee ◽  
Cezary Szczylik ◽  
Jahangeer Malik ◽  
...  
Keyword(s):  
Clear Cell ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
First Line ◽  
Open Label ◽  
Cell Renal Cell Carcinoma ◽  
Duration Of Response ◽  
Prior Systemic Therapy

4570 Background: KEYNOTE-427 (NCT02853344) is an open-label, single-arm, phase 2 study to evaluate efficacy and safety of first-line single-agent pembro, a programmed death 1 (PD-1) inhibitor, in patients (pts) with ccRCC (cohort A) and non–clear cell RCC (cohort B). Updated follow up from cohort A are presented. Methods: Pts with histologically confirmed ccRCC, measurable per RECIST v1.1, and no prior systemic therapy were eligible. Pts received pembro 200 mg IV Q3W for 2 y or until confirmed progressive disease, unacceptable toxicity, or pt decision to withdraw. Primary end point was objective response rate (ORR; per RECIST v1.1 blinded independent central review). Additional end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: 110 pts enrolled; median (range) follow-up was 18.0 (2.5-22.7) mo. Median age (range) was 64 (29-87); 38.2%, 47.3%, and 14.5% had favorable, intermediate, and poor IMDC risk, respectively; 47.3% were PD-L1 positive. Confirmed ORR was 36.4% with 3 (2.7%) CRs and 37 (33.6%) PRs. Median DOR was not reached. Median PFS was 7.1 mo (95% CI, 5.6-11.0) and median OS was not reached. Results by IMDC category are outlined in the table. By PD-L1 status, confirmed ORR was 44.2% and 29.3% for positive and negative, respectively. By sarcomatoid differentiation (n=11), confirmed ORR was 63.6%. Treatment-related AEs occurred in 80.9%, with pruritus (28.2%) and fatigue (28.2%) most commonly reported. One pt died of treatment-related pneumonitis. Conclusions: With a median 18-months’ follow up, first-line pembro monotherapy continued to show antitumor activity in pts with ccRCC. Meaningful responses were observed in pts with intermediate/poor IMDC risk, PD-L1 positive and sarcomatoid differentiated tumors. Safety profile was comparable to previously reported. Clinical trial information: NCT02853344. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document