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.

Interim safety and clinical activity in patients (pts) with locally advanced and unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase I study of ramucirumab (R) plus durvalumab (D).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 92-92 ◽  
Author(s):  
Yung-Jue Bang ◽  
Talia Golan ◽  
Chia-Chi Lin ◽  
Yoon-Koo Kang ◽  
Zev A. Wainberg ◽  
...  
Keyword(s):  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Primary Objective ◽  
Clinical Activity ◽  
Duration Of Treatment ◽  
Serious Adverse Event ◽  
Previously Treated ◽  
Grade 3 ◽  
Ecog Ps

92 Background: Angiogenesis and immunosuppression are hallmarks of tumor growth. This global phase 1 trial evaluates the combination of R (anti-VEGFR2) and D (anti-PD-L1) in pts with G/GEJ by simultaneously targeting these two processes. Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT02572687) enrolled pts with confirmed G/GEJ adenocarcinoma with prior progression on 1 or 2 lines of systemic therapy, measurable disease, ECOG PS 0-1, and baseline tumor tissue. PD-L1 expression was assessed using the SP-263 IHC; MSI status was determined using PCR. Enrolled pts received R (8 mg/kg IV) and D (750 mg IV) every two weeks on a 28-day cycle. Primary objective was to assess safety and tolerability of R+D; preliminary efficacy was also examined. Results: As of 26-May-2017, 29 G/GEJ adenocarcinoma pts were treated. The median age was 55 y; 69% were male; 66% had ECOG PS of 1; 48% had PD-L1 ≥25% expression in tumor or immune cells, 3.5% were MSI-high; and 72% received study treatment as second line for advanced disease. Median duration of treatment was 2.5 mo for R and 3.0 mo for D. Treatment-emergent adverse events (TEAEs) occurred in 29 (100%) pts and 21 (72%) pts experienced grade 3/4 TEAEs, while treatment-related AEs (TRAE) occurred in 24 (83%) pts; none resulted in treatment discontinuation. Ten (35%) pts had grade 3 TRAEs, and no grade 4 or 5. All grade TRAEs occurring in ≥10% of pts were hypertension (34%), fatigue (31%), headache (24%), diarrhea (21%), pyrexia (10%) and decreased appetite (10%). Five pts (17%) reported a serious adverse event related to study treatment. Preliminary efficacy data (RECIST v1.1) showed 5 of 29 pts (17%) achieved a confirmed PR. Only 1 responding pt was MSI high. The overall response rate for pts with PD-L1 ≥25% was 36%. Median PFS was 2.6 mo (95% CI, 1.45 to 6.28). As of data cut-off, 6 pts (21%) remain on treatment. Conclusions: R+D generated no unexpected toxicity, and demonstrated antitumor activity in pts with previously treated advanced G/GEJ adenocarcinoma. Clinical trial information: NCT02572687.

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.

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.

Pharmacokinetics and safety of an oral ALK inhibitor, ASP3026, observed in a phase I dose escalation trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2602-2602 ◽  
Author(s):  
Amita Patnaik ◽  
Patricia LoRusso ◽  
Howard A. Ball ◽  
Erkut Bahceci ◽  
Geoffrey Yuen ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Expansion Phase ◽  
Advanced Malignancies ◽  
Grade 3 ◽  
Ecog Ps ◽  
Clinical Trial Information

2602 Background: ASP3026 (3026) is a selective, potent, ATP-competitive, small molecule oral inhibitor of ALK receptor tyrosine kinase that has not previously been tested in humans. A Phase 1 dose-escalation trial, using a 3+3 design, evaluating 3026 as an oral single agent was conducted to investigate PK (Day 1 and Day 28), safety and clinical activity in patients (pts) with advanced malignancies (excluding leukemias) of ECOG PS 2 or less. Methods: 3026 was administered under fasting conditions on a continuous schedule to pts in successive dose-escalating cohorts at doses ranging from 25 mg QD to 800 mg QD. Results: Thirty pts were enrolled into the dose escalation part of the study. The MTD was determined based on DLT data from cycle 1. Three DLTs were observed: grade 2 nausea and vomiting leading to dose reduction at 525 mg QD; grade 3 rash leading to dose reduction, and grade 3 ALT/AST increase leading to study withdrawal at 800 mg QD. The most common AEs were constipation, vomiting, diarrhea, nausea and abdominal pain, and all AEs were manageable and reversible. Median AUC and Cmax increased proportionally with dose from 25 mg QD to 800 mg QD. There was no evidence of non-linear PK at ASP3026 doses >25 mg QD. The median terminal half-life was approximately 10 - 41 hours. Overall, A3026 appears well absorbed with median Tmax around 3 hours for both Day 1 and Day 28. Terminal T1/2 appears adequate for one daily dosing with median values ranging from approximately 18 to 34 hours. Based on visual inspection of pre-dose (trough) values from Days 8, 15, 22, and 28 it appears that steady-state conditions are achieved by day 28. Conclusions: The MTD of 3026 is 525 mg QD. Treatment with 3026 resulted in a promising safety and PK profile in pts with advanced malignancies. Further evaluation of 3026 in pts with tumors harboring gene mutation or ALK fusion genes in the cohort expansion phase at the MTD is ongoing. Clinical trial information: NCT01401504.

Ramucirumab (R) plus pembrolizumab (P) in treatment naive and previously treated advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: A multi-disease phase I study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4046-4046 ◽  
Author(s):  
Ian Chau ◽  
Johanna C. Bendell ◽  
Emiliano Calvo ◽  
Rafael Santana-Davila ◽  
Hendrik-Tobias Arkenau ◽  
...  
Keyword(s):  
Median Duration ◽  
Gastroesophageal Junction ◽  
Survival Rates ◽  
Kidney Injury ◽  
Primary Objective ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Grade 3 ◽  
Ecog Ps ◽  
Clinical Trial Information

4046 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: Ongoing, multi-cohort, phase 1a/b trial enrolled pts with G/GEJ adenocarcinoma, measurable disease, ECOG PS 0-1, previously treated (Cohorts A and B) or untreated (Cohort A2) for advanced disease. PD-L1 was positive (tumor proportion score [TPS] ≥1%) or negative (TPS < 1%) using the DAKO PD-L1 22C3 IHC pharmDx assay. R was administered at 8 mg/kg on Days 1&8 (Cohorts A and A2) or 10 mg/kg on Day 1 (Cohort B) with P 200 mg on Day 1 q3W. Primary objective- assess safety and tolerability of R+P; preliminary efficacy will be examined. Results: As of 21-Nov-2016, 41 previously treated G/GEJ pts were enrolled. Median age was 58 y, 76% male, 66% had ECOG PS of 1, 46% were PD-L1+, and 59% received study treatment as third or subsequent line. Median duration on therapy was 2.8 mo and 4.1 mo for A and B, respectively. Overall, 33 (80%) pts experienced a treatment-related AE (TRAE) and similar between cohorts A and B. Ten (24%) pts experienced grade 3-4 TRAEs, most commonly colitis (7%) and hypertension (7%). One treatment-related death occurred (pneumonitis and pulmonary sepsis). Responses occurred in 3 (7%) pts with 46% disease control rate (DCR). Progression-free and overall survival rates at 6 mo were 22.4 % (95% CI, 9.8-38.0) and 51.2% (95% CI, 33.9-66.1) respectively. Nine (22%) pts remain on treatment. Eighteen of 25 planned treatment naïve G/GEJ pts were enrolled. Median age was 70 yr, 83% male, 56% had ECOG PS of 0, and PD-L1 status is pending. Median duration on therapy was 2.1 mo. Twelve (67%) pts experienced a TRAE. Grade 3 TRAEs occurred in 5 (28%) pts (hypertension [n = 3], diarrhea, and acute kidney injury). No grade 4-5 events occurred. Preliminary efficacy data showed 3 (17%) pts responded with 50% DCR. Median PFS is immature and 89% of pts remain on treatment. Conclusions: R+P generated no new safety signals and demonstrated encouraging antitumor activity in treatment naïve and previously treatedadvanced G/GEJ adenocarcinoma. Clinical trial information: NCT02443324.

A phase I study of APL-501, an anti-PD-1 antibody, in patients with recurrent or advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15125-e15125
Author(s):  
Mark Voskoboynik ◽  
Gary Edward Richardson ◽  
Linda R. Mileshkin ◽  
Catriona M. McNeil ◽  
Lisa Horvath ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Receptor Occupancy ◽  
Median Number ◽  
Unknown Primary ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Grade 3 ◽  
Refractory Solid Tumor ◽  
Ecog Ps

e15125 Background: APL-501 is a humanized monoclonal antibody targeting programmed cell death-1 (PD-1). APL-501 is being evaluated in patients (pts) with advanced recurrent and relapsed solid tumors who had not been previously treated with an immune checkpoint inhibitor in an ongoing 3-part Phase 1 trial (NCT03053466). Herein, we present the emerging pharmacokinetic (PK) and receptor occupancy (RO), safety and preliminary efficacy. Methods: Weight-based dose escalation (1, 3, and 10 mg/kg, Part 1) and Extension (Part 2) has been completed and the study is currently enrolling specific tumor types (MSI-H/dMMR and Carcinoma of Unknown Primary [CUP]) into the Expansion Cohorts (Part 3). Relapsed/refractory solid tumor pts were enrolled in Part 1 and Part 2. Key exclusion criteria included prior therapy targeting PD-1/PD-L1 and uncontrolled CNS metastases. APL-501 was administered IV over 1 hour every 14 days. Serum and PBMCs were collected for PK and RO analysis, respectively. RO was assessed using different T-cell markers measured by flow cytometry of PBMC. Anti-tumor activity was assessed by investigators using RECIST and irRECIST. Safety was assessed using CTCAE, v4.03. Results: As of 31 Dec 2019, 22 pts were enrolled with a mean age of 62.1 (SD: 12.2) years. ECOG PS 0/1 reported at 10/12 pts, respectively. Pts had a median number of 3 prior lines of therapy (range, 1 – 9) and median time to treatment from initial diagnosis was 30.1 months (range, 6.7 – 184.8). Across doses evaluated, APL-501 demonstrated dose proportional PK. One hundred percent (100%) RO was observed across all doses evaluated. No dose limiting toxicities were reported. Fifteen pts (68.2%) had related AEs; two pts (9.1%) had Grade ≥ 3 related AEs to APL-501. Eight pts had stable disease and two pts had partial response by RECIST (esophageal adenocarcinoma and CUP). Seven pts remained on therapy for ≥ 24 weeks. The recommended phase 2 dose (RP2D) has been determined to be 400 mg IV every 14 days (non-weight-based) based on safety and PK modeling. Conclusions: Preliminary results indicate clinical activity of APL-501 in relapsed/refractory malignant disease with a generally tolerable safety profile. The PK and RO profile, across all doses evaluated, appears comparable to marketed PD-1 inhibitors. Continued exploration of APL-501 with the RP2D in CUP and MSI-H/dMMR tumors is being planned. Clinical trial information: NCT03053466 .

Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4071-4071 ◽  
Author(s):  
Zev A. Wainberg ◽  
Neil Howard Segal ◽  
Dirk Jaeger ◽  
Kyung-Hun Lee ◽  
John Marshall ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Safety Profile ◽  
Phase 1 ◽  
Primary Objective ◽  
Clinical Activity ◽  
Open Label ◽  
Sorafenib Treatment ◽  
Secondary Objective ◽  
Pugh Class ◽  
Grade 3

4071 Background: Durvalumab, an anti-PD-L1 mAb, has shown early and durable clinical activity with manageable safety in an ongoing Phase 1/2, multicenter, open-label study in pts with advanced solid tumors. Interim analyses from the HCC cohort in the dose-expansion part of this study are reported here. Methods: Patients with HCC (Child-Pugh class A) received durvalumab 10 mg/kg i.v. q2w for 12 months or until confirmed progressive disease, whichever occurred first. The primary objective was to evaluate the safety profile; secondary objective was to assess the antitumor activity (investigator-assessed RECIST v1.1). Clinical activity was evaluated for the total HCC population and by viral status. Results: As of Oct 24 2016, 40 HCC pts with median 23.9 (range 2.4–34.7) weeks follow-up received durvalumab. 93% had prior sorafenib. Treatment-related AEs occurred in 80.0% of pts, most commonly fatigue (27.5%), pruritus (25.0%) and elevated aspartate aminotransferase (AST) (22.5%). Grade 3–4 treatment-related AEs were reported in 20.0% of pts, most commonly elevated AST (7.5%) and elevated alanine aminotransferase (5.0%). 7 (17.5%) pts completed the initial 12-month treatment and 7 (17.5%) pts discontinued treatment because of an AE (none related to treatment). There were no deaths due to treatment-related AEs. Clinical activity is presented in the table. 4 pts achieved a PR; 2 were ongoing at data cut-off. Conclusions: Durvalumab had an acceptable safety profile and showed promising antitumor activity and OS in pts with HCC, particularly HCV+ pts. Clinical trial information: NCT01693562. [Table: see text]

Interim results of a phase 1/2 study of JNJ-63723283, an anti-PD-1 monoclonal antibody, in patients with advanced cancers.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 58-58 ◽  
Author(s):  
Emiliano Calvo ◽  
Victor Moreno ◽  
Enriqueta Felip ◽  
Giuseppe Curigliano ◽  
Daniel Morgensztern ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Pleural Effusion ◽  
Phase 1 ◽  
Study Drug ◽  
Clinical Activity ◽  
Phase 2 ◽  
Duration Of Treatment ◽  
Safety And Efficacy ◽  
Grade 3

58 Background: JNJ-63723283 (JNJ-283), an anti-programmed cell death protein-1 antibody, enhances T cell-mediated cytokine induction and reduces tumor volume in preclinical models. A phase 1/2 study is ongoing to evaluate the safety and efficacy of JNJ-283 in patients (pts) with advanced cancers. Methods: Eligible pts have advanced or refractory solid tumor malignancies. Phase 1 dose escalation starting from 80 mg Q2W was supported by a modified continual reassessment method to identify the recommended phase 2 dose(s) (RP2D). Safety and efficacy of the RP2D(s) will be evaluated in phase 2. Pharmacokinetics (PK), receptor occupancy (RO) and other pharmacodynamic parameters were assessed. Results: As of data cut-off, 32 pts were treated with JNJ-283 80 mg (n = 4), 240 mg (n = 16) or 460 mg (n = 4) Q2W, or 480 mg (n = 8) Q4W; 16 pts remain on study drug. Median duration of treatment was 58 days (range 16 – 240). Median age was 56 years (range 27 - 80) and median prior lines of therapy was 3 (range 1 - 12). One dose-limiting toxicity of grade 3 pleural effusion was reported at 240 mg Q2W. An RP2D of 240 mg Q2W is being evaluated in phase 2. Most common adverse events (AEs) were anemia (28.1%), hypertension (28.1%), diarrhea (21.9%) and hyponatremia (21.9%). Observed serious AEs were pleural effusion, pneumonia and chest pain (6.3% each). Infusion-related AEs of nausea and rash occurred in 6.3% of pts each. Immune-related AEs (irAEs) were reported in 21.8% of pts and were mostly grade 1-2; grade 3 irAEs included pleural effusion, pneumonitis, AST increased and ALT increased. One pt discontinued treatment due to a treatment-related AE. Three pts achieved a partial response at 240 mg Q2W; 18 pts achieved stable disease or better. Preliminary serum JNJ-283 concentrations demonstrated linear PK with dose-proportional increases and interpatient variability generally consistent with monoclonal antibody therapeutics. Preliminary circulating T cell RO demonstrated dose-independent saturation. Conclusions: JNJ-283 displayed a well-tolerated safety profile with preliminary antitumor activity in pts with advanced cancers. The trial is ongoing to further characterize the safety, PK and clinical activity of JNJ-283. Clinical trial information: 2016-002017-22.

A Sequential Two-Stage Dose Escalation Study Evaluating The Safety and Efficacy Of Eltrombopag In Thrombocytopenic Patients With Myelodysplastic Syndrome (MDS) Resistant To Hypomethylating Agents (HMA)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2760-2760 ◽  
Author(s):  
Rami S Komrokji ◽  
Vu H. Duong ◽  
Ling Zhang ◽  
Ji-Hyun Lee ◽  
Eric Padron ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Median Duration ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Primary Objective ◽  
Duration Of Treatment ◽  
Dose Escalation Study ◽  
Grade 3

Abstract Introduction Thrombocytopenia remains a critical management challenge for MDS pts. The outcome of MDS Pts after HMA failure is poor. Eltrombopag is an oral, small non-peptide thormbopoeitin (TPO) receptor agonist. It has biologically distinct effects in part to its binding site on the TPO receptor that is distinct from that for native TPO and other synthetic agonists. We conducted an investigator initiated study with eltrombopag in MDS pts with thrombocytopenia after HMA failure. Methods The study is a phase 1, dose escalation design. Pts are allocated to dose cohorts of 50, 100, 150, 200, 250 and 300mg/day. Each dose cohort includes 6 pts. Key eligibility criteria include confirmed diagnosis of MDS or acute myeloid leukemia (AML) with 20-30% myeloblasts. Pts must have at least one prior HMA treatment. The mean platelet count within a month of enrollment must be ≤ 50 X 109 /L. Key exclusions include splenic enlargement > 8 cm, bone marrow fibrosis ≥ grade 3, and prior TPO agonist use. The primary objective of the study is to determine the MTD. Dose-limiting toxicity (DLT) is defined as treatment related non-hematological grade 3-4 toxicity. If no DLTs were observed during the first 2 cycles of therapy, the next cohort of patients receives a higher dose of eltrombopag. Pts who did not receive treatment for 8 weeks were replaced for DLT assessment. The secondary endpoints include response, overall survival (OS) and leukemia free survival (LFS). Results Thirty-one pts were enrolled. Table-1 summarizes baseline characteristics. Most pts had higher risk MDS who were heavily pretreated. The median interval from MDS diagnosis was 28 months. Six pts were enrolled in cohort 1 (50 mg), 10 pts in cohort 2 (100 mg) (4 pts replaced (2 deaths unrelated to treatment, 1 infection, 1 progressive disease (PD)), 12 pts were enrolled in cohort 3 (150 mg) where 6 pts were replaced (5 PD and 1 infection), and to date, 3 pts are enrolled in cohort 4 (200 mg). No protocol defined DLT have been encountered to date. No grade 3 or 4 treatment related adverse events have been reported. The most common adverse events that were deemed possibly, or probably related to study drug included fatigue (n=9), diarrhea (n=6), night sweats (n=3), headache (n=3), numbness (n=3). There were 2 pts with grade 2 pneumonia and grade 3 fatigue, and 2 grade 2 diarrhea events. Seven pts (23%) developed leukocytosis on treatment and 13 pts (42%) experienced an increase in circulating myeloblasts at some point during study treatment. Three of 27 pts developed higher grade bone marrow myelofibrosis (change from grade 0-1 to grade 2-3), one of whom received the 50 mg dose and 2 pts on the150 mg dose. Eleven pts (35%) progressed to AML, 9 out of 11 patients who progressed had RAEB-2 or RAEB-t and 5 had poor risk cytogenetics. The median follow up duration is 23 months. The best response on study per IWG 2006 criteria include marrow CR (mCR) + Hematological improvement (HI) (6%, n=2), mCR (3%, n=1), HI (13%, n=4), stable disease (SD) (29%, n=9), PD (36%, n=11) and not evaluable for response (13%, n=4). The overall response rate (HI+) was 22% (7 out 31 pts) and 26% among pts evaluable for response (7 out of 27 pts). HI included 6 platelet responses and 1 erythroid response. Among 20 pts who were platelet transfusion dependent, 6 became transfusion independent (30%). The median duration of response was 3.3 months. The median duration of treatment is 2 months. The most common reasons for eltrombopag discontinuation were PD (48%) and infection (10%). Median OS was 5 months whereas median OS was 8 months among HI+ responders. The median LFS was 3.5 months. Conclusions Eltrombopag yielded modest responses in heavily treated higher risk MDS pts after HMA failure. Leukocytosis, increased circulating myeloblasts and myelofibrosis were observed in subsets of pts. Future development of eltrombopag as a single agent in MDS should be in lower risk MDS or in combination with HMA in higher risk MDS. Disclosures: Off Label Use: Use of eltrombopag in MDS.

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