Early safety and efficacy from a phase I open-label clinical trial of CD137(4-1BB) agonistic antibody LVGN6051 as monotherapy and in combination with pembrolizumab.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2521-2521
Author(s):  
Siqing Fu ◽  
Wael A. Harb ◽  
Sapna Pradyuman Patel ◽  
Charles Lu ◽  
Daniel M. Halperin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Safety Profile ◽  
Single Agent ◽  
Human Study ◽  
Hepatic Metastases ◽  
Preliminary Evidence ◽  
Open Label ◽  
Grade 3 ◽  
Favorable Safety

2521 Background: LVGN6051, a monoclonal antibody against CD137 (also known as 4-1BB or TNFRSF9) with an engineered Fc capable of selectively binding to the Fcγ receptor IIB, acts as a conditional CD137 agonist, resulting in immune activation optimally in tumor microenvironment ( Qi, Nat. Commun. 2019 ). In preclinical models, LVGN6051 demonstrated robust anti-tumor efficacy and safety as a single agent and in combination with anti-PD-1 antibodies. Therefore, we have initiated this first-in-human study of LVGN6051 alone or in combination with pembrolizumab for the treatment of advanced or metastatic malignancy. Methods: This study includes accelerated dose escalation monotherapy up to 2 mg/kg of LVGN6051, and traditional 3 + 3 design for higher doses of LVGN6051 alone or in combination with pembrolizumab. Then, this study will enroll patients with specific types of malignancies following Simon’s two-stage design. Both agents are administered once every 3 weeks. Primary objectives of this study were to define the safety profile and to establish the recommended phase 2 dose (RP2D) of LVGN6051 alone or in combination with pembrolizumab. Pharmacokinetics, immunogenicity, pharmacodynamics and clinical efficacy will be also evaluated. Results: At the cut-off date on January 18, 2021, 16 subjects have been enrolled into the monotherapy cohorts (n=12, no DLT observed up to 7 mg/kg), and the combination cohort (n=4, ongoing at LVGN6051 2 mg/kg and pembrolizumab 200 mg, one DLT observed). No treatment-related adverse event (TRAE) was observed in monotherapy. Treatment-emergent adverse events (TEAE) in combination included increased ALT/AST, thrombocytopenia, and fatigue. In the combination cohort, one patient with predominant hepatic metastases and history of intermittent grade 2 hepatic impairment experienced grade 3 increased ALT/AST (DLT) on cycle 1 day 15 that were resolved to her baseline without corticosteroids on cycle 1 day 18. TRAE included increased ALT/AST, thrombocytopenia, neutropenia, nausea and fatigue. Seven of 10 evaluable patients in the monotherapy cohorts demonstrated stable disease with the longest treatment being 8+ months. Tumor reductions by >10% were observed in melanoma and neuroendocrine tumor on monotherapy. One patient with metastatic head and neck squamous cell carcinoma who had progressed on an anti-PD-L1 based therapy showed an immune partial response (iPR) for 6+ months to the combination therapy. Conclusions: Preliminary evidence showed that LVGN6051 was well tolerated and tumor shrinkages were observed. While we continue assessing its safety profile, antitumor activity was observed in the LVGN6051 and pembrolizumab cohort. The favorable safety profile and preliminary antitumor activity warrant further evaluation in patients with advanced malignancies. Clinical trial information: NCT04130542.

A phase 1b, open-label, dose-escalation study to evaluate camidanlumab tesirine (Cami) as monotherapy in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2556-2556
Author(s):  
Igor Puzanov ◽  
Patricia LoRusso ◽  
Kyriakos P. Papadopoulos ◽  
Christopher T. Chen ◽  
Yvan LeBruchec ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Single Agent ◽  
Treatment Withdrawal ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1B ◽  
Grade 3

2556 Background: Depletion of tumor-infiltrating CD25+ regulatory T cells (Tregs), which inhibit tumor-specific immune responses, could contribute to tumor eradication. Cami (ADCT-301), an anti-CD25, pyrrolobenzodiazepine-based antibody-drug conjugate, targets CD25+ Tregs. A mouse surrogate has shown potent antitumor activity in solid tumor models. Here we report preliminary data from the monotherapy arm of a phase 1b trial of Cami in pts with selected advanced solid tumors. Methods: The monotherapy dose-escalation part of this open-label study enrolled pts (aged ≥18 years) with selected advanced solid tumors and no suitable existing therapy. The primary objective was to characterize safety and tolerability, and to identify the recommended phase 2 dose of Cami monotherapy. Secondary and exploratory objectives included evaluation of preliminary antitumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. Pts received Cami every 3 weeks (1 cycle) with dose escalation per a 3+3 design. Disease control rate (DCR) was assessed (complete and partial responses [CR, PR] and stable disease). Results: At data cut-off (Dec 17, 2020), 44 pts were enrolled, with primary tumor types (stage IVA/B: 27 pts; 61.4%) of colorectal (15 pts; 34.1%), pancreatic (14 pts; 31.8%), head and neck, ovarian/fallopian tube, and renal cell carcinoma (all 3 pts; 6.8%), non-small cell lung cancer (2 pts; 4.5%), gastric, esophageal/GEJ, melanoma, and triple-negative breast cancer (each 1 pt; 2.3%). Median (range) age was 60.5 (33–82) years; median (range) number of prior systemic therapies was 4 (1–9). Pts received a median (range) of 2 (1–6) Cami cycles at doses of 20–150 µg/kg. Median (range) treatment duration was 22 (1–178) days. No dose-limiting toxicities were reported. The maximum tolerated dose (MTD) was not reached. All-grade treatment-emergent adverse events (TEAEs) in ≥20% pts were nausea (18 pts; 40.9%), decreased appetite and fatigue (each 16 pts; 36.4%), constipation (13 pts; 29.5%), abdominal pain (11 pts; 25%), and rash (10 pts; 22.7%). The only Grade ≥3 TEAE in ≥10% pts was anemia (5 pts; 11.4%). Grade 3 autoimmune AEs (colitis, immune-mediated AE, systemic inflammatory response syndrome) and neurologic AEs (dysphagia and asthenia, but not GBS) were reported in 3 (6.8%) and 2 (4.5%) pts, respectively. 1 (2.3%) Cami-related TEAE led to treatment withdrawal; no Cami-related TEAEs were fatal. DCR was 25% (95% CI: 11.1, 34.7); 11/44 pts attained stable disease. No pts had CR or PR. Conclusions: Dose escalation of Cami monotherapy is complete. The safety profile is encouraging and MTD was not reached. PK/PD data will be presented. 150 µg/kg is the highest dose investigated for single-agent Cami and the highest to be investigated combined with pembrolizumab in selected advanced solid tumors in the current protocol. Funding: ADC Therapeutics SA NCT03621982. Clinical trial information: NCT03621982.

Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2512-2512 ◽  
Author(s):  
Amita Patnaik ◽  
Soonmo Peter Kang ◽  
Anthony W. Tolcher ◽  
Drew Warren Rasco ◽  
Kyriakos P. Papadopoulos ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Preliminary Evidence ◽  
Open Label ◽  
Dose Escalation Study ◽  
Advanced Malignancy ◽  
Multiple Tumor ◽  
Label Dose ◽  
Grade 3 ◽  
Tumor Types

2512 Background: Programmed death-1 (PD-1) is an inhibitory T-cell coreceptor that may lead to suppression of antitumor immunity. MK-3475 is a humanized monoclonal IgG4 antibody against PD-1. Preclinically, MK-3475 has shown antitumor activity in multiple tumor types. This first-in-human phase I trial explored safety, PK, PD, and antitumor activity of MK-3475. Methods: An open-label, dose escalation study was conducted in patients with advanced malignancy refractory to standard therapy. Cohorts of 3-6 patients were enrolled (3+3 design) at escalating IV doses of 1, 3, and 10 mg/kg. Following an initial dose and 28-day Cycle 1, patients were allowed to subsequently receive multiple doses given every 2 wks. Radiographic assessment was conducted every 8 wks using RECIST 1.1 guidelines. Results: Nine patients, 3 at each dose level, completed the dose-limiting toxicity (DLT) period (28 d). Patients had non–small cell lung cancer (NSCLC, n=3), rectal cancer (n=2), melanoma (MEL, n=2), sarcoma (n=1), or carcinoid (n=1). To date, a total of 63 doses were administered (median 7/patient; max 12) without DLT. Drug-related adverse events (AEs) across all doses included Grade 1 fatigue (n=3), nausea (n=2), diarrhea (n=1), dysgeusia (n=1), breast pain (n=1), and pruritus (n=1). One drug-related Grade 2 AE of pruritus was reported. No drug-related AEs ≥ Grade 3 were observed. PK data are shown in the table. Based on RECIST, 1 patient with MEL on therapy >6 mths had a partial response, and preliminary evidence of tumor size reduction (stable disease) was observed in 3 additional patients with advanced cancer. Conclusions: MK-3475 was well-tolerated without DLT across 3 tested dose levels. Evidence of antitumor activity was observed. Enrollment continues to obtain additional safety, PK, and efficacy data; updated data will be presented at the meeting. [Table: see text]

BMS-986205, an indoleamine 2, 3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (nivo): Updated safety across all tumor cohorts and efficacy in advanced bladder cancer (advBC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 358-358 ◽  
Author(s):  
Jason J. Luke ◽  
Josep Tabernero ◽  
Anthony Joshua ◽  
Jayesh Desai ◽  
Andrea I. Varga ◽  
...  
Keyword(s):  
Phase 1 ◽  
Preliminary Evidence ◽  
Stevens Johnson Syndrome ◽  
Tumor Escape ◽  
Open Label ◽  
Indoleamine 2 ◽  
Johnson Syndrome ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Favorable Safety

358 Background: Nivo (anti–PD-1) has shown durable responses and manageable safety (ORR, 19.6%; grade 3‒4 treatment-related AEs [TRAEs], 18%) in advBC (Sharma et al. Lancet Oncol 2017), but prolonging survival in more pts requires additional approaches to overcome tumor evasion mechanisms. IDO1 allows tumor escape through kynurenine (KYN) production, which stimulates regulatory T cells and suppresses effector T-cell proliferation. Anti─PD-1 can upregulate IDO1, supporting the rationale for combining nivo with an IDO1i. BMS-986205 is a selective, potent, once-daily (QD) oral IDO1i that works early in the IDO1 pathway to reduce KYN production. BMS-986205 + nivo showed favorable safety and efficacy in heavily pretreated pts with select solid tumors (Luke et al. SITC 2017; NCT02658890). Updated safety across all tumor cohorts and efficacy in the immuno-oncology (I-O)–naive advBC cohort are reported. Methods: Dose-escalation methods in this phase 1/2a, open-label study were previously described; during expansion, pts received BMS-986205 100 or 200 mg QD + nivo 240 mg IV Q2W or 480 mg IV Q4W. Objectives included safety and ORR by RECIST v1.1 (includes unconfirmed responses). Results: As of Mar 2018, 516 pts received BMS-986205 + nivo; 45% had ≥2 prior regimens. TRAEs occurred in 57% of pts (grade 3‒4, 12%), the most common being fatigue (15%) and nausea (12%); 19 pts (4%) discontinued due to TRAEs, and 3 pts ( < 1%) died due to a TRAE (myocarditis, Stevens-Johnson syndrome, and hepatic failure). In all treated pts and within the advBC cohort (n = 30), the frequency and severity of TRAEs and rate of discontinuation due to TRAEs was lower with the 100- vs 200-mg BMS-986205 dose. Among the 27 pts with I-O–naive advBC, with a median duration of follow-up of 24 wk, ORR was 37% (3 CRs, 7 PRs), and the DCR was 56%; ORR in pts with tumor PD-L1 ≥1% (Dako PD-L1 IHC 28-8 pharmDx assay; n = 14) vs < 1% (n = 10) was 50% vs 30%. Conclusions: BMS-986205 + nivo was well tolerated in heavily pretreated pts, and tolerability was improved with the 100-mg BMS-986205 dose. Preliminary evidence of efficacy was observed in advBC, supporting further evaluation of BMS-986205 + nivo. Clinical trial information: NCT02658890.

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]

Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius).

2015 ◽  
Vol 33 (18_suppl) ◽  
pp. LBA8512-LBA8512 ◽  
Author(s):  
Sagar Lonial ◽  
Brendan M. Weiss ◽  
Saad Zafar Usmani ◽  
Seema Singhal ◽  
Ajai Chari ◽  
...  
Keyword(s):  
Median Time ◽  
Alkylating Agents ◽  
Single Agent ◽  
Open Label ◽  
Prior Therapy ◽  
Duration Of Response ◽  
Grade 3 ◽  
International Multicenter Study ◽  
Line Of Therapy ◽  
Favorable Safety

LBA8512 Background: DARA, a human anti-CD38 IgG1κ mAb, has single agent activity and is well-tolerated in rel/ref MM (Lokhorst HM et al. ASCO 2014). This ongoing phase 2 study (NCT01985126) evaluated DARA monotherapy in the FDA breakthrough therapy designation population: MM patients with ≥ 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or double refractory to a PI and IMiD. Preliminary results are reported. Methods: MMY2002 is a 2-part, open-label, international, multicenter study. In part 1 stage 1, 34 patients were randomized to DARA 8 mg/kg (n = 18) q4w or 16 mg/kg (n = 16) qw x 8 wk, q2w x 16 wk, then q4w in a Simon-2-stage design to determine the most effective dose. Subsequently, 90 additional patients were enrolled in the 16 mg/kg DARA group. The primary endpoint was overall response rate (ORR) by independent review (IRC). Results: Data for the 16 mg/kg DARA group are presented (n = 106). Baseline characteristics: median time since diagnosis, 4.8 y; median prior treatment lines, 5; 75% ISS ≥ 2. Refractory to: last line of therapy, 96%; last PI and IMiD, 95%; pomalidomide, 63%: carfilzomib, 48%; alkylating agents, 78%. Adverse events (AE; ≥ 20%) were fatigue (39.6%), anemia (33.0%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), cough (20.8%). Infusion-related reactions (IRR, 42.5%) were mainly grade 1/2 during first infusion (grade 3 4.7%; no grade 4). No patients discontinued study due to IRRs; 5 (4.7%) discontinued treatment due to AEs. None of these AEs were assessed by the investigator to be DARA-related. ORR (IRC assessed) was 29.2%, with 3 sCR, 10 VGPR, and 18 PR with a 7.4 month median duration of response. ORR was consistent across clinically relevant subgroups. Median time to progression was 3.7 months. Median overall survival has not been reached and the estimated 1-year OS rate is 65%. After a median follow up of 9.4 months 14/31 (45.2%) of responders remain on therapy. Conclusions: In a heavily pre-treated MM population (95% refractory to last PI and IMiD), DARA at 16 mg/kg showed meaningful durable single agent activity, with deep responses and a favorable safety profile. Clinical trial information: NCT01985126.

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.

A phase I study of JS001, a humanized IgG4 mAb against programmed death-1 (PD-1) in patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3067-3067 ◽  
Author(s):  
Zhihong Chi ◽  
Bixia Tang ◽  
Xinan Sheng ◽  
Lu Si ◽  
Chuanliang Cui ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Tumor Infiltrating Lymphocytes ◽  
Complete Response ◽  
Open Label ◽  
Tumor Biopsy ◽  
Elimination Half ◽  
Grade 3 ◽  
Approved Drugs ◽  
Favorable Safety

3067 Background: JS001 blocks the interaction between PD-1 and its ligands and eradicates established tumor in human PD-1 Knock-in mouse model. Methods: A Phase I open-label study is designed to evaluate the safety and tolerability of JS001 in advanced solid tumor pts who are refractory to standard therapy. The study has a 3+3 dose escalation design with planned cohorts at 1, 3, and 10 mg/kg followed by a dose expansion. (Clinical Trial ID: NCT02836795). Results: As of January 27, 2017, pts enrollment has been completed with 36 pts from 3 indications (22 Melanoma; 9 Urothelial Carcinoma; 5 Renal Cell Carcinoma). The majority of melanomas are acral and mucosal origin. No DLT was observed and no MTD was reached in the study. The most common treatment-related AEs were grade 1/2, including hyper- or hypo-thyroidism (42%), rash (39%), fever (28%), leukopenia (22%), elevation of liver enzymes (19%), anorexia (17%), and fatigue (14%). Treatment–related grade 3 AEs include proteinuria (n = 1), and lipase increase (n = 2). The emergence of AEs is not dose related. JS001 PK shows dose-dependent exposure with the elimination half-life of 6 to 12 days. Among 32 evaluable pts, 1 pt have complete response (melanoma), 6 pts have partial response (3 melanoma, 2 RCC and 1 UC), and 10 pts achieve stable disease, for an ORR of 22% and a DCR of 53%. 6 out of 7 CR/PR pts still have ongoing response. Two groups of pts benefited most from JS001 treatment, pts with high tumor-infiltrating lymphocytes (TIL) (50% ORR) and pts with > 1% PD-L1 expression in tumor biopsy (46% ORR). Conclusions: JS001 exhibited a favorable safety profile in human. Treatment related AEs are in line with those from approved drugs in the same class. JS001 has demonstrated promising anti-tumor activity, especially in previously under-evaluated acral (20% ORR, 53% DCR) and mucosal (25% ORR, 50% DCR) melanomas. Clinical trial information: NCT02836795.

Significant antitumor activity for low-dose ipilimumab (IPI) with pembrolizumab (PEMBRO) immediately following progression on PD1 Ab in melanoma (MEL) in a phase II trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10004-10004 ◽  
Author(s):  
Daniel Olson ◽  
Jason J. Luke ◽  
Andrew Stewart Poklepovic ◽  
Madhuri Bajaj ◽  
Emily Higgs ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Primary Endpoint ◽  
Response Rate ◽  
Progression Free Survival ◽  
Open Label ◽  
Free Survival ◽  
Prior Therapy ◽  
Length Of Treatment ◽  
Grade 3

10004 Background: Combination PD1 + CTLA4 antibodies (Abs) shows greater response rate (RR) versus PD1 Ab alone in MEL, but RR after initial PD1 Ab progression awaits robust investigation. CTLA4 Ab alone after PD1 Ab progression has a historical RR of 13%. We report final results of the first prospective clinical trial evaluating IPI 1mg/kg + PEMBRO immediately following progression on PD1 Ab (NCT02743819). Methods: Patients (pts) with advanced MEL, no prior CTLA4 Ab for metastatic disease, and who had progressed on PD1 Ab as immediately prior therapy (or non-CTLA4 Ab combination) were eligible. Pts received PEMBRO 200 mg + IPI 1 mg/kg Q3W for 4 doses, then PEMBRO alone for up to two years. The primary endpoint was RR by irRECIST. After 35 pts, the study met its primary endpoint with 10/22 evaluable pts achieving a response. The trial was expanded to enroll a total of 70 pts in open-label accrual to further describe the RR for this regimen in an exploratory fashion. The data analysis cutoff was January 30, 2020. Results: 67/70 accrued patients were evaluable for treatment response. Prior treatments included 60 on PD1 Ab alone and 10 on PD1 Ab-based combinations. Of these, 10 pts had progressed in the adjuvant setting. Median length of treatment on prior PD1 Ab was 4.8 months. Response assessments included 4 CR, 17 PR and 16 SD for a RR of 31% (21/67) in evaluable pts, and 30% (21/70) in all enrolled pts. 4 pts with a PR and 6 with SD had unconfirmed responses making the irRECIST response rate 25% (17/67) and 24% (17/70) among evaluable and enrolled pts, respectively. Median progression free survival (PFS) was 4.7 mo (95% CI: 2.8-8.3) and PFS at six months was 45% (95% CI: 33%-57%). 15/70 (21%) pts experienced ≥ grade 3-4 drug-related AEs, the most common being diarrhea, rash and transaminase elevation. PD-L1 positive vs negative status from historical tumor specimens did not associate with RR. Conclusions: This is the largest prospective study of IPI 1mg/kg + PEMBRO, demonstrating significant antitumor activity and tolerability in MEL post-PD1 Ab. Clinical trial information: NCT02743819.

386 Phase I/Ib first-in-human study of HEK-NIZ985, a recombinant IL-15/IL-15Rα heterodimer, alone and in combination with spartalizumab, in adults with advanced and metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A411-A411
Author(s):  
Rom Leidner ◽  
Andrea Wang-Gillam ◽  
Sumati Gupta ◽  
Robert Wesolowski ◽  
Douglas McNeel ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Single Agent ◽  
Human Study ◽  
Primary Objective ◽  
Time Dependent ◽  
Open Label ◽  
Dose Proportional

BackgroundHEK-NIZ985 (NIZ985) is a recombinant heterodimer of IL-15/IL-15Rα that expands effector lymphocytes and antitumor activity in animal models and a human clinical trial. We report interim data from the first-in-human study of NIZ985.MethodsCNIZ985X2102J is an open-label Phase I/Ib dose-escalation/expansion trial evaluating the safety of subcutaneous NIZ985 three-times-weekly (TIW; 2-weeks-on/2-weeks-off) or once-weekly (QW; 3-weeks-on/1-week-off) as a single agent (SA) or in combination (CM) dosing with 400 mg of the PD-1 inhibitor spartalizumab every 4 weeks, in adults with metastatic/unresectable solid tumors. SA dosing was 0.25–4 µg/kg TIW or 2–10 µg/kg QW; CM dosing was 1 µg/kg TIW or 2–4 µg/kg QW. The primary objective was to characterize the safety and tolerability of NIZ985 ± spartalizumab. Data are presented for dose escalation, and CM-TIW expansion.ResultsOverall, 83 patients entered dose escalation (n=47) or CM-TIW expansion (n=36), of whom 63.8% (30/47) and 69.4% (25/36), respectively, had received ≥3 prior lines of antineoplastic treatment. At data cut-off (March 2, 2020), 91.6% (76/83) had discontinued study treatment. Adverse events (AEs) are summarized below (table 1). There were no dose-limiting toxicities during the first 28-day cycle in any cohort. Systemic skin AEs (Cycle 2) occurred in three SA-TIW patients receiving 2 or 4 µg/kg (bullous pemphigoid, purpura, vasculitis), limiting TIW escalation and initiating QW dose exploration; these were not observed at 1 µg/kg TIW (± spartalizumab) or for QW doses up to 10 µg/kg. CM-TIW dose expansion was therefore at 1 µg/kg; the recommended QW expansion dose is currently undetermined. For SA NIZ985, best overall response (RECIST 1.1) was stable disease (SD; 8/27 patients [29.6%]). Objective responses for NIZ985 plus spartalizumab (3/56 partial response [PR; 5.3%], 15/56 SD [26.8%]) occurred in both immuno-oncology treatment (IO)-naïve and IO-experienced patients, including 5/8 IO-experienced melanomas (cutaneous: 3 SD, 1 PR; uveal: 1 SD). Systemic NIZ985 exposure was approximately dose-proportional after first dose for ≥1 µg/kg TIW and <10 µg/kg QW, with time-dependent clearance without accumulation. Proliferation of peripheral CD8+ and NK lymphocytes, and increased inflammatory cytokines, were observed for both dosing schedules.Abstract 386 Table 1Adverse event summaryConclusionsNIZ985 is safe and tolerable at both TIW and QW dosing ± spartalizumab. It displays approximately dose-proportional, time-dependent PK, and a biomarker and lymphocyte response profile consistent with target engagement. Limited antitumor activity was reported during dose escalation; however, preliminary responses in both IO-experienced and IO-naïve patients were seen in combination with spartalizumab that warrant further investigation.Ethics ApprovalThe study was approved by an independent ethics committee and/or institutional review board at each participating site.

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