CheckMate 8KX: Phase 1/2 multitumor preliminary analyses of a subcutaneous formulation of nivolumab (± rHuPH20).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2575-2575
Author(s):  
Sara Lonardi ◽  
Iwona Lugowska ◽  
Christopher G. C. A. Jackson ◽  
Anne O'Donnell ◽  
Rastilav Bahleda ◽  
...  
Keyword(s):  
De Novo ◽  
Phase 1 ◽  
Geometric Mean ◽  
Primary Objective ◽  
Tumor Type ◽  
Part D ◽  
Part C ◽  
Local Site ◽  
Survival Expectations ◽  
Grade 3

2575 Background: Immunotherapy has transformed cancer survival expectations. Nivolumab (NIVO), a programmed death-1 inhibitor, is approved for intravenous (IV) administration across multiple cancers. BMS is developing a subcutaneous (SC) NIVO formulation with a permeation enhancer, recombinant human hyaluronidase PH20 enzyme (rHuPH20), to allow for more rapid delivery and the potential to decrease treatment burden. We report the first data on pharmacokinetics (PK), pharmacodynamics, safety, and immunogenicity for SC NIVO + rHuPH20. Methods: CheckMate 8KX is a phase 1/2 study in checkpoint inhibitor-naïve patients (pts) who were ≥ 18 years of age, ECOG PS 0–1, with metastatic/unresectable solid tumors and measurable disease. The primary objective was to describe SC NIVO PK; secondary objectives were safety and immunogenicity. Additional analyses compared exposures to historical IV NIVO (Zhao X, et al. J Clin Oncol 2020;31:302–309). In cycle 1, pts in Part A received SC NIVO 720 mg + rHuPH20, and pts in Part B received SC NIVO 720 mg, SC NIVO 960 mg + rHuPH20, or SC NIVO 960 mg. For cycles 2+, pts in Parts A and B received IV NIVO 480 mg every 4 weeks (Q4W). Pts still on study switched to Part C, SC NIVO 1200 mg + rHuPH20 until end of therapy. In Part D, pts received de novo SC NIVO 1200 mg + rHuPH20 Q4W. Results: Patient characteristics varied by age, weight, tumor type, and prior treatment. NIVO exposures increased with increasing SC dose (Table). For 960 mg and 1200 mg NIVO + rHuPH20, Cavg and Ctau were above geometric mean exposures for IV NIVO 3 mg/kg every 2 weeks (Q2W), and Cmax was below IV NIVO 10 mg/kg Q2W. In Part C (n = 28), 13 (46.4%) pts experienced any-grade TRAEs with no new/worsening grade 3+ TRAEs or TRAEs leading to discontinuation/death; 7 (25.0%) reported grade 1 local site reactions. In Part D (n = 36), 27 (75.0%) pts experienced any-grade TRAEs, 4 (11.1%) grade 3/4 TRAEs, 2 (5.6%) serious grade 3/4 TRAEs with 1 leading to discontinuation, and no treatment-related deaths; 10 (27.8%) reported grade 1 local site reactions. Anti-NIVO antibodies (Ab) were observed with SC NIVO but not associated with altered PK/safety, or neutralizing Ab. Exploratory biomarker data found increased CD8+ tumor-infiltrating lymphocytes and PD-L1 tumor expression in post-treatment biopsies, similar to IV NIVO. Conclusions: Exposures associated with SC NIVO + rHuPH20 doses investigated in CheckMate 8KX were well tolerated, with a safety profile consistent with IV NIVO. Data support evaluation of SC NIVO + rHuPH20 in a phase 3 study. Clinical trial information: NCT03656718. [Table: see text]

The combination of venetoclax, lenalidomide, and rituximab in patients with newly diagnosed mantle cell lymphoma induces high response rates and MRD undetectability.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7505-7505
Author(s):  
Tycel Jovelle Phillips ◽  
Alexey Valeryevich Danilov ◽  
David Alan Bond ◽  
Alex Francisco Herrera ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase 1 ◽  
Safety Data ◽  
Standard Of Care ◽  
Primary Objective ◽  
Clinical Activity ◽  
Newly Diagnosed ◽  
Grade 5 ◽  
Unrelated Condition ◽  
Mantle Cell ◽  
Grade 3

7505 Background: MCL is a rare lymphoma without a standard of care but several regimens have demonstrated clinical activity, the majority based on traditional chemotherapy. We hypothesized that adding venetoclax (V) to R2 would be safe and effective in MCL pts irrespective of age, morphology or stage. Here we present safety and efficacy data from the on-going phase 1b study of R2 + V in pts with newly diagnosed MCL. Methods: This multi-center phase 1 study (NCT03523975) enrolled pts aged ≥18 yrs with untreated MCL. The primary objective was to characterize the safety and tolerability of R2 + V and determine the MTD. During induction (12 months (m)) pts received lenalidomide (L) 20 mg daily on day 1-21, Rituximab (R) was given weekly during c1 then on day 1 of every even cycle, V was escalated over 4 weeks to 400 mg beginning day 8. Each cycle is 28 days (d). The DLT period was 42 d beginning C1D8. In maintenance, R every 8 weeks for 36m, L at 10 mg or half of last dose during induction for 24 m and V for minimum 12 m. No pts have been transplanted. Pts with progression (PD) came off study. MRD was analyzed in parallel with scans during induction by clonoSEQ assay (Adaptive Biotechnologies). Results: As of Feb. 1st, 2021, we have enrolled all 28 planned pts on study. Pt characteristics/responses are summarized in Table. Among the 28 pts who have received at least one dose, the median treatment duration so far is 278d (IQR 170-560), with 24 pts still on treatment (Tx). 1 pt is off from a unrelated condition. All pts escalated to V 400 mg w/o any DLTs noted. Treatment-emergent adverse events (TEAEs) were reported in 100% of pts, and grade 3+ TEAEs were reported in 26 (93%) patients. The most common all-grade TEAEs (≥50% of pts), regardless of relationship to study Tx, were fatigue, neutropenia and diarrhea. Grade ≥3 TEAEs reported in ≥50% pts were neutropenia (68%) and thrombocytopenia (50%). No pts have withdrawn or d/c Tx due to AEs. There was one grade 5 event, in a non-evaluable pt, related to a PE that occurred prior to DLT period. In the 28 evaluable pts the ORR (CR/PR) was 96% (27/28 pts) with CR/CRu of 89%. Of the responding pts, two had PD, one w/ CR and one w/ PR. All pts with PD had baseline TP53 mutation. MRD testing was successful in all pts. At time of submission 20 of 28 (71%) were MRD - at 10-6. Conclusions: Interim results show that at the MTD the combination of V 400 mg daily, L 20 mg, with R is safe with a manageable toxicity profile and a high ORR and MRD - in pts with newly diagnosed MCL. Safety data is consistent with the AE profile noted for each drug without any unexpected or unique AEs. Updated results including BH3 profiling will be presented at the meeting. Clinical trial information: NCT03523975. [Table: see text]

ANCHOR (OP-104): Melflufen plus dexamethasone (dex) and bortezomib (BTZ) in relapsed/refractory multiple myeloma (RRMM)—Optimal dose, updated efficacy and safety results.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8037-8037
Author(s):  
Roman Hajek ◽  
Luděk Pour ◽  
Miquel Granell ◽  
Vladimir Maisnar ◽  
Paul G. Richardson ◽  
...  
Keyword(s):  
Partial Response ◽  
Cardiac Failure ◽  
Alkylating Agents ◽  
Phase 1 ◽  
Optimal Dose ◽  
Complete Response ◽  
Primary Objective ◽  
Clinical Activity ◽  
Development Of Resistance ◽  
Grade 3

8037 Background: Development of resistance to standard treatments for RRMM highlights the need for novel therapies. Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen + dex showed clinical activity and an acceptable safety profile in HORIZON (Richardson et al. J Clin Oncol. 2020 Dec 9 [Epub]). This is an update of the BTZ arm of the phase 1/2a ANCHOR study (NCT03481556). Methods: Patients (pts) with RRMM were intolerant or refractory to a prior IMiD, with 1-4 prior lines of therapy (LoTs). Prior treatment with a proteasome inhibitor (PI) was allowed, but pts could not be refractory to PIs in the last LoT. Melflufen (30, 40, or 20 mg intravenously; d 1 of each 28-d cycle) was administered with BTZ (1.3 mg/m2 subcutaneous) + oral dex (20 mg on d 1, 4, 8, and 11 and 40 mg on d 15 and 22; dex dose reduced if aged ≥ 75 y). The primary objective in phase 1 was to determine the optimal phase 2 dose of melflufen for this combination. Results: As of the data cutoff date (October 19, 2020), 13 pts received melflufen (30 mg, n = 6; 40 mg, n = 7) + dex and BTZ. In the 30 mg and 40 mg cohorts, respectively, median age was 78.5 y (range, 70-82) and 70.0 y (range, 61-76); median prior LoTs was 3.5 (range, 2-4) and 2.0 (range, 1-4); 33% and 50% of evaluable pts had high-risk cytogenetics; 83% and 71% were refractory to last LoT; 100% and 86% received a prior PI; 33% and 14% were refractory to PIs. In the 30 mg and 40 mg cohorts, respectively, median treatment duration was 6.5 mo (range, 1.4-29.0) and 8.7 mo (range, 2.1-19.6); 4 (67%) and 4 pts (57%) were still on treatment; 2 and 3 pts discontinued (30 mg: progressive disease [PD] and other [1 pt each]; 40 mg: adverse event [AE], lack of efficacy, and PD [1 pt each]). Confirmed overall response rate in the 30 mg and 40 mg cohorts, respectively, was 50% (1 very good partial response [VGPR] and 2 partial response [PR]) and 71% (1 complete response, 3 VGPR, and 1 PR). Most common grade 3/4 treatment-related AEs (TRAEs) were thrombocytopenia (30 mg: 50%; 40 mg: 100%) and neutropenia (30 mg: 33%; 40 mg: 71%); grade 3/4 nonhematologic TRAEs were infrequent; 3 pts discontinued study treatment due to treatment-emergent AEs (30 mg: cardiac failure chronic and osteolysis [1 pt each]; 40 mg: thrombocytopenia [1 pt]). Serious TRAEs occurred in 2 pts (33%) in the 30 mg cohort (neutropenia and pneumonia [1 pt], syncope [1 pt]) and 1 pt (14%) in the 40 mg cohort (thrombocytopenia and neutropenia). No dose-limiting toxicities occurred at either dose level. Fatal AEs occurred in 1 pt in the 30 mg cohort (cardiac failure chronic; unrelated to study treatment). Conclusions: ANCHOR determined that the optimal dose of melflufen is 30 mg + dex and BTZ; results showed clinical activity in heavily pretreated pts. Recruitment is ongoing; updated data will be presented. Clinical trial information: NCT03481556.

scholarly journals Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer

2020 ◽  
Vol 38 (6) ◽  
pp. 1836-1845
Author(s):  
Shunsuke Kondo ◽  
Masaomi Tajimi ◽  
Tomohiko Funai ◽  
Koichi Inoue ◽  
Hiroya Asou ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Mammalian Target Of Rapamycin ◽  
Japanese Patients ◽  
Competitive Inhibitor ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Dual Inhibitor ◽  
Advanced Malignancies ◽  
Grade 3

Summary LY3023414 is an oral, selective adenosine triphosphate-competitive inhibitor of class I phosphatidylinositol 3-kinase isoforms, mammalian target of rapamycin, and DNA-protein kinase in clinical development. We report results of a 3 + 3 dose-escalation Phase 1 study for twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to evaluate tolerability and safety of LY3023414. Secondary objectives were to evaluate pharmacokinetics and to explore antitumor activity. A total of 12 patients were enrolled and received 150 mg (n = 3) or 200 mg (n = 9) LY3023414 BID. Dose-limiting toxicities were only reported at 200 mg LY3023414 for 2 patients with Grade 3 stomatitis. Common treatment-related adverse events (AEs) across both the dose levels included stomatitis (75.0%), nausea (66.7%), decreased appetite (58.3%), diarrhea, and decreased platelet count (41.7%), and they were mostly mild or moderate in severity. Related AEs Grade ≥ 3 reported for ≥1 patient included anemia, stomatitis, hypophosphatemia, and hyperglycemia (n = 2, 16.7%). Two patients discontinued due to AEs (interstitial lung disease and stomatitis). No fatal events were reported. The pharmacokinetic profile of LY3023414 was characterized by rapid absorption and elimination. Five patients had a best overall response of stable disease (150 mg, n = 3; 200 mg, n = 2) for a 55.6% disease control rate. LY3023414 up to 200 mg BID is tolerable and safe in Japanese patients with advanced malignancies.

A phase 1 trial of FID-007, a novel nanoparticle paclitaxel formulation, in patients with solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3021-3021
Author(s):  
Jacob Stephen Thomas ◽  
Diane Habib ◽  
Diana L. Hanna ◽  
Irene Kang ◽  
Syma Iqbal ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Topical Therapy ◽  
Maculopapular Rash ◽  
Primary Objective ◽  
Multiple Tumor ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Proportional

3021 Background: FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. In addition to allowing the drug to remain in solution until it can enter a cancer cell, the PEOX nanoparticle preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. In xenograft studies, FID reduced or limited tumor growth in multiple tumor types including lung, gastric, breast, pancreatic, and ovarian cancer. FID was more effective at lower or comparable taxane doses with fewer side effects. We present the first-in-human trial of FID. Methods: The study is evaluating the safety, PK, and efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 125mg/m2 using a standard 3+3 dose escalation design. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and no more than 3 prior lines of cytotoxic therapy for advanced disease. Results: Twenty-five pts were treated across 6 dose levels. Median age was 62 (44-76). ECOG PS was 2 in 1 pt and 1 in 64%. Median number of cycles was 2 (1-16). There were 2 DLTs of grade 3 rash at 100 mg/m2. Given the transient nature of the rash and response to topical therapy, DLT definition was modified to exclude grade 3 rash that lasts ≤ 7 days and additional patients were treated at 100 mg/m2 which was deemed tolerable. There was 1 DLT of grade 3 neutropenia at 125 mg/m2. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts were rash (64%), alopecia (52%), pruritus (44%), anemia (44%) leukopenia, fatigue (40% each), dysgeusia, anorexia, nausea (32% each), and neutropenia (28%). Grade 3/4 TRAEs occurring in > 1 pt were anemia (20%), neutropenia, leukopenia, and maculopapular rash (16%). There were no treatment discontinuations due to toxicity. Twenty-two pts were evaluable for response by RECIST 1.1 with a PR rate of 14% (PR in pancreatic, biliary tract and NSCLC) and disease control rate of 59%. PK is linear and dose proportional. There is no paclitaxel accumulation after weekly dosing, and the t1/2 is between 18-26 hours. Conclusions: FID has a manageable safety profile with MTD not reached. Accrual is continuing at 125 mg/m2. PK is linear, dose proportional and comparable to that of nab-paclitaxel. There is preliminary evidence of anti-tumor activity in heavily pre-treated pts across different tumor types. Enrollment in dose escalation continues. Combination studies with immunotherapeutic agents are planned. Clinical trial information: NCT03537690.

Tolerability of split-dose oprozomib (ONX 0912) in patients with advanced refractory or recurrent solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13077-e13077
Author(s):  
Kyriakos P. Papadopoulos ◽  
David S. Mendelson ◽  
Anthony W. Tolcher ◽  
Howard A. Burris ◽  
Michael S. Gordon ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Solid Tumors ◽  
Phase 1 ◽  
Dose Schedule ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Status Change ◽  
Dose Escalation Study ◽  
Split Dose ◽  
Grade 3

e13077 Background: Oprozomib (ONX0912), a structural analog of carfilzomib, is an orally bioavailable proteasome inhibitor that irreversibly binds to its target and is being evaluated in hematologic malignancies and solid tumors (ST). In a dose-escalation study of once-daily (qd) ONX0912, the maximum tolerated dose (MTD) was 150 mg/d. The protocol was subsequently amended to investigate the effects of a split-dose schedule. Presented here are the interim results from this patient (pt) group. Methods: This is an ongoing, phase 1 study in pts with advanced refractory or recurrent ST. The primary objective is to evaluate the safety and tolerability of ONX0912 and determine the MTD. ONX0912 is administered for 5 consecutive days in 14-day cycles. For pts under the amended regimen, treatment is initiated at 60 mg BID, with 4–6 h between doses. Daily doses are escalated in 30 mg increments in successive groups of 3 pts. Groups are expanded to include 6 pts in the event of a dose-limiting toxicity (DLT) or if the MTD is reached. All AEs, including serious AEs (SAEs), are defined per protocol and collected from screening to 30 days after the last dose. Results: 13 pts received a split dose of ONX0912 (4 pts: 60 mg BID; 3 pts: 90/60 mg; 6 pts: 90 mg BID). At least 1 dose reduction was required by 1 pt in the 90/60 mg group and 2 pts in the 90 mg BID group. 9 pts reported treatment-related GI AEs (vomiting, n=9; nausea, n=8; diarrhea, n=5). 2 SAEs, arthralgia and mental status change, were reported at 60 mg BID. 2 SAEs resulting in a dose delay were reported at 90/60 mg (Grade 3/4 anemia [ongoing, also required a dose reduction] and reversible fatigue). There was 1 DLT at 90 mg BID (Grade 3 reversible hypophosphatemia), and this cohort was therefore expanded. Treatment-related vomiting led to discontinuation for 1 patient at 60 mg BID. No AEs led to early withdrawal, and no deaths have been reported in the study. Conclusions: With qd administration, the MTD of ONX0912 was established at 150 mg/d. However, the MTD has not been reached on the split-dose regimen at cumulative doses up to 180 mg/d (90 mg BID). GI AEs were the most common treatment-related AEs. Based on these preliminary observations, split-dose ONX0912 may improve tolerability over qd dosing.

Evaluating the addition of bevacizumab (Bev) to endocrine therapy as first-line treatment for hormone-receptor positive (HR+)/HER2-negative advanced breast cancer (ABC): Pooled-analysis from the LEA (GEICAM/2006-11_GBG51) and CALGB 40503 (Alliance) trials.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1012-1012
Author(s):  
Miguel Martin ◽  
Sibylle Loibl ◽  
Terry Hyslop ◽  
Juan de la Haba-Rodriguez ◽  
Bahriye Aktas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Randomized Trials ◽  
De Novo ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
Primary Objective ◽  
Cox Models ◽  
Hormone Receptor Positive ◽  
Grade 3 ◽  
Ongoing Support

1012 Background: Data from randomized trials comparing ET v ET-Bev in 1st line HR+/HER2- ABC pts showed controversial results. We performed a pooled-analysis of two randomized trials (LEA and CALGB 40503) to refine the Bev value in this patient population. Methods: We analysed 749 ABC pts with ET (letrozole-673, tamoxifen-39, fulvestrant 250mg-37) +/- Bev. Primary objective was to compare progression-free survival (PFS). Secondary endpoints were: safety; other efficacy (overall response rate [ORR], clinical benefit rate [CBR] and overall survival [OS]) in all pts; and efficacy in de novo pts and by previous endocrine-sensitivity (-/+ 24 months [mo] without recurrence under ET in adjuvant setting). Multivariable Cox models were fitted for PFS adjusted by study co-variables and controlled for study level differences. Results: Median age was 61 years (yr) (range: 25-87); 40% had de novo ABC and 60% recurrent disease (with disease free interval of ≤ 1 yr in 5%, 1-2 yr in 7% and > 2 yr in 88%); 82% of recurrent pts had previous ET sensitivity. Median PFS was 14.3 mo in the ET arm v 19 mo in the ET+Bev arm (HR 0.77; 95% CI 0.66-0.91; p<0.01). ORR and CBR with ET v ET+Bev were 40 v 61% (p<0.01) and 64 v 77% (p<0.01). OS did not differ between arms (HR 0.96; 95% CI 0.77-1.18; p=0.68). PFS for de novo ABC pts was 14.6 and 19.3 mo in the ET and ET+Bev arms (HR 0.82; 95% CI 0.63-1.06; p=0.13). PFS differed between arms for previous sensitive pts (HR 0.68; 95% CI 0.53-0.89; p=0.004) but not for ET-resistant pts (HR 0.73; 95% CI 0.4-1.3; p=0.29). Grade 3-5 hypertension (2.2 v 20.1%), proteinuria (0 v 9.3%), cardiovascular events (0.5 v 4.2%) and liver events (0 v 2.9%) were significantly higher in the ET+Bev arm (all p<0.01). Multivariable analyses showed age (p<0.01), PgR status (p<0.01), type of prior ET (p<0.01) and treatment arm (p<0.01) to be associated with PFS. Conclusions: The addition of Bev to ET increased PFS but not OS. Analyses to define subgroups with prolonged benefit from ET alone or ET-Bev are ongoing. Support: U10CA180821, U10CA180882, Breast Cancer Research Foundation, Genentech, Roche. Clinical trial information: NCT00545077 / NCT00601900.

Interim safety and clinical activity in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase 1 study of ramucirumab (R) plus pembrolizumab (P).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 102-102 ◽  
Author(s):  
Ian Chau ◽  
Johanna C. Bendell ◽  
Emiliano Calvo ◽  
Rafael Santana-Davila ◽  
Jordi Rodon Ahnert ◽  
...  
Keyword(s):  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Maculopapular Rash ◽  
Pneumocystis Pneumonia ◽  
Primary Objective ◽  
Clinical Activity ◽  
Duration Of Treatment ◽  
Dosing Regimens ◽  
Grade 3 ◽  
Ecog Ps

102 Background: Angiogenesis and immunosuppression are hallmarks of tumor growth. This is the first study to combine R (anti-VEGFR2) with P (anti-PD-1) to simultaneously target both processes in the tumor microenvironment. Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT02443324) enrolled pts with confirmed G/GEJ adenocarcinoma with prior progression on systemic therapy, measurable disease, ECOG PS 0-1, and baseline tumor tissue. PD-L1 was classified as positive (≥1%) or negative using the DAKO PD-L1 22C3 IHC pharmDx assay. Two dosing regimens were evaluated, Cohort A (R 8 mg/kg on Days 1&8) and Cohort B (R 10 mg/kg on Day 1), given with P 200 mg on Day 1 q3W. The primary objective was to assess safety and tolerability of adding R to P; preliminary efficacy will be examined. Results: As of 23-Jun-2016, 40 G/GEJ pts have been enrolled (Cohort A: n=23; Cohort B: n=17). First pt treated in Cohorts A and B were on 29-Feb-2016 and 26-Oct-2015, respectively. The median age was 59 y, 75% were male, 65% had ECOG PS of 1, 48% were PD-L1 positive, and 70% received study treatment as third or subsequent regimen. Median duration of treatment was 2.1 mo and 4.1 mo for Cohort A and B, respectively. All grades treatment-related AEs (TRAE) occurred in 31 (78%) pts and similar between cohorts; TRAEs in ≥10% of pts were fatigue (30%), infusion related reaction (12.5%), decreased appetite (12.5%), pruritus (10%), maculopapular rash (10%), and hypertension (10%). Ten (25%) pts had grade 3-4 TRAEs, most commonly colitis (7.5%) and hypertension (7.5%). One treatment-related death occurred (pneumocystis pneumonia and pulmonary sepsis). Preliminary efficacy data showed 3 of 40 (7.5%) pts (PD-L1 negative, n=1; PD-L1 positive, n=2) have responded (1 confirmed and 2 unconfirmed PR) to treatment with a 45% disease control rate. Median PFS was 2.10 mo (95% CI, 1.18 to 4.04) and 2.60 mo (1.38, NR) for Cohorts A and B, respectively. Fifteen (37.5%) pts, including all responders, remain on treatment. Conclusions: R+P generated no new safety signals and demonstrated antitumor activity in pts with previously treated advanced G/GEJ adenocarcinoma. Clinical trial information: NCT02443324.

Primary analysis of phase 2 results of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with locally advanced cutaneous squamous cell carcinoma (laCSCC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6015-6015 ◽  
Author(s):  
Michael Robert Migden ◽  
Nikhil I. Khushalani ◽  
Anne Lynn S. Chang ◽  
Danny Rischin ◽  
Chrysalyne D. Schmults ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Median Duration ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Primary Objective ◽  
Phase 2 ◽  
Primary Analysis ◽  
Curative Surgery ◽  
Grade 3

6015 Background: Cemiplimab (REGN2810) produced substantial antitumor activity with durable responses in Phase 1 CSCC expansion cohorts and Phase 2 metastatic (m) CSCC cohort. We now present the primary analysis of the Phase 2 laCSCC cohort (NCT02760498; data cutoff date: Oct 10, 2018). Methods: Pts with laCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 78 pts were enrolled (59 M/ 19 F; median age: 74 years; ECOG PS: 0 in 38 pts, 1 in 40 pts; primary CSCC site: head/neck in 79.5%; prior systemic therapy: 15.4%; prior radiotherapy: 55.1%). Median duration of follow-up was 9.3 months (range: 0.8–27.9). ORR by central review was 43.6% (95% CI: 32.4–55.3; 10 CRs and 24 PRs); investigator-assessed (INV) ORR was 52.6% (95% CI: 40.9–64.0; 13 CRs and 28 PRs). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 24.2 months and was still ongoing. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.8% (95% CI: 51.1–73.5). Median observed time to response was 1.9 months (range: 1.8–8.8). Median progression-free and overall survival have not been reached. Tumor PD-L1 status is available for 48/78 pts, tumor mutational burden analysis (from targeted exome panel) is ongoing for ≥40/78 pts; response correlation analyses are planned. The most common treatment-emergent adverse events (AEs; all grades, Grade ≥3) were fatigue (42.3%, 1.3%), diarrhea and pruritus (both 26.9%, 0%), and nausea (21.8%, 0%). INV grade ≥3 immune-related AEs occurred in 10.3% of pts. One pt died due to an unknown cause that was assessed as treatment-related. Conclusions: Cemiplimab 3 mg/kg Q2W showed substantial antitumor activity, durable responses, and acceptable safety profile in pts with laCSCC. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or laCSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.

NCI9782: A phase 1 study of talazoparib in combination with carboplatin and paclitaxel in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14640-e14640
Author(s):  
Anita Ahmed Turk ◽  
Ticiana Leal ◽  
Nancy Chan ◽  
Robert Wesolowski ◽  
Kristen Renee Spencer ◽  
...  
Keyword(s):  
Phase 1 ◽  
Parp Inhibitor ◽  
Parp Inhibition ◽  
Tumor Type ◽  
Strand Breaks ◽  
Grade 5 ◽  
Common Grade ◽  
Grade 3 ◽  
Dna Strand ◽  
Platinum Chemotherapy

e14640 Background: Poly(ADP-ribose) polymerase (PARP) enzymes are involved in DNA repair and activated by DNA strand breaks. DNA damage from carboplatin is associated with activation of PARP. Preclinical data indicate that PARP inhibition and trapping potentiates the anti-tumor effect of platinum chemotherapy. Talazoparib (T) is an oral, selective PARP inhibitor. This phase I study combines T with carboplatin (C) and paclitaxel (P). Methods: Two dosing schedules are being investigated. C is administered on day 1 and P on days 1, 8, and 15 of a 21-day cycle. T (100-1000mcg) is dosed once daily for days 1-7 (schedule A) or days 1-3 (schedule B). Dose escalation is by 3+3 design. Patients (pts) must have tumor type that is expected to respond to C + P or have BRCA germline or somatic mutation and adequate organ function. After 4-6 cycles of combination therapy, pts may continue the combination, change to C and intermittent T without P or change to T alone. Each schedule will have a 6 pt dose expansion at the MTD. The dose level (DL) 1 for schedule B is the previously reported MTD from schedule A (T 250mcg with C AUC 6 + P 80mg/m2). Results: Schedule B results are reported: 15 pts (median age 56 yrs [range 43-76]) have been enrolled. Primary malignancies include colorectal (4), pancreas (4), prostate (2), urothelial (2), and other (3). Dose was initiated at Schedule A MTD. DL2 (T 350mcg with C AUC 6 + P 80mg/m2) exceeded the MTD with 2 of 6 pts experiencing hematologic dose limiting toxicities (DLTs). DL1 is the confirmed schedule B MTD. Dose expansion to 6 pts is ongoing. Of the 11 pts with measurable disease, 3 (27%) had PR and 5 (45%) had SD. Pts were on study a median of 10 weeks (range 5-36+). Most common grade 3/4 AEs include leukopenia (53%), neutropenia (47%), and anemia (47%). One grade 5 AE of intracranial hemorrhage occurred, possibly related to therapy in the setting of grade 3 thrombocytopenia and concern for CNS disease. Conclusions: The schedule B MTD and RP2D is T 250 mcg with C AUC 6 and P 80mg/m2. Data from the full dose expansion will be presented. This combination was tolerated with prolonged responses seen at lower dose T in combination with C+P. Clinical trial information: NCT02317874.

Initial results of a phase III investigation of safety/efficacy of nivolumab and ABI-009 (nab-sirolimus) in advanced undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), chondrosarcoma (CS), osteosarcoma (OS), and Ewing sarcoma.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 21-21
Author(s):  
Victoria S. Chua-Alcala ◽  
Katherine Kim ◽  
Nupur Assudani ◽  
Ahmad Al-Shihabi ◽  
Doris Quon ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Dose Finding ◽  
Phase Iii ◽  
Phase 2 ◽  
Undifferentiated Pleomorphic Sarcoma ◽  
Pleomorphic Sarcoma ◽  
Grade 3

21 Background: Objectives: (1) To investigate the MTD of ABI-009 when given with nivolumab, a PD-1 inhibitor, in previously treated advanced undifferentiated pleomorphic sarcoma, liposarcoma, chondrosarcoma, osteosarcoma and Ewing sarcoma; (2) To investigate the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of this combination therapy in the above mentioned patient group, and (3) To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: This is an IRB approved protocol with 2 parts. The Phase 1 part is a dose-finding study using the “cohort of three design”, wherein standard doses of nivolumab 240 mg is 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. The starting dose of ABI-009 is 56 mg/m2, and sequentially escalating doses are 75, and 100 mg/m2. The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: The Phase 1 part of study is closed, after 9 patients were treated successfully at 3 dose levels. 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 (n=3): Grade 3 treatment-related adverse events (TRAEs) included hyperdyslipidemia (n=1), and hyperglycemia (n=1). At Dose 2 (n=3): Grade 3 TRAEs included increased ALT (n=1). At Dose 3 (n=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. Conclusions: The primary objective has been met with no DLTs, the MTD was not reached and Dose 3 has been designated as the phase 2 dose of ABI-009 which is on-going. Clinical trial information: NCT03190174.

Sign in / Sign up

Export Citation Format

Share Document