CX-072 (pacmilimab), a Probody® PD-L1 inhibitor, in advanced or recurrent solid tumors (PROCLAIM-CX-072): an open-label dose-finding and first-in-human study

BackgroundProbody® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing ‘off-tumor’ toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1).MethodsIn the dose-escalation phase of this multicenter, open-label study (NCT03013491), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1).ResultsAn MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, >50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1).ConclusionsPacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression.Trial registration numberNCT03013491.

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Phase I study of the combination of alisertib (MLN8237) and gemcitabine in advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3589 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3589-3589

Author(s):

Jasmine Huynh ◽

Justin Chen ◽

Edward Jae-Hoon Kim ◽

David R. Gandara ◽

Thomas John Semrad ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Pancreatic Adenocarcinoma ◽

Dose Escalation ◽

Stable Disease ◽

Phase I Study ◽

Open Label ◽

Expansion Phase ◽

Grade 3 ◽

Advanced Pancreatic Adenocarcinoma

3589 Background: Aurora Kinase A (AKA) is a key mitotic regulator overexpressed in multiple solid tumors. This open-label dose escalation and expansion phase I study evaluated the safety and tolerability of alisertib (MLN8237), an oral AKA inhibitor, in combination with gemcitabine. Methods: In dose escalation, patients (pts) > 18y with refractory solid tumors received 28-day cycles of gemcitabine on days 1, 8, 15 and alisertib twice daily on days 1-3, 8-10, and 15-17. Gemcitabine was given at 1000mg/m2. Four dose levels (DL) of alisertib (20-50mg) were given per 3+3 design to investigate dose limiting toxicities (DLT) in cycle 1, to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D). In dose expansion, advanced pancreatic adenocarcinoma pts received the MTD dose twice daily on a modified dosing schedule to allow for pharmacokinetic (PK) evaluation. Anti-tumor activity was assessed by response rate (RECIST 1.1) and progression-free survival (PFS). PK evaluation of plasma gemcitabine and alisertib was performed on all pts enrolled in the dose expansion. PK sampling was performed before treatment, immediately after gemcitabine infusion, and at other pre-specified post-infusion timepoints. Results: Twenty-six pts were treated in total: 21 pts in dose escalation and 5 pts in dose expansion. Overall, median age was 57y [42-82]; 50% male; 62% PS 1 (16 pts); 2 [0-7] median prior therapies. In the dose escalation phase, 9 tumor types were included and NSCLC was most common (7 pts). Maximum administered dose (DL4) achieved 900 mg alisertib per cycle and was tolerated (1 DLT in 6 pts). The dose expansion phase enrolled 5 pts with advanced pancreatic adenocarcinoma; median age 63y [48-82]; 60% male; 60% PS 1 (3 pts); 2 [1-2] median prior therapies. Grade ≥3 TRAEs were observed in 73% of all pts and were predominantly hematologic, including neutropenia (54%), leukopenia (50%), and lymphopenia (31%). Similar TRAEs were seen at DL4; all 14 pts experienced neutropenia with 64% experiencing grade ≥3 neutropenia. Fourteen of 23 evaluable pts (61%) had stable disease and 2 pts (9%) had partial response (PR) as best overall response. Median PFS was 2.9 months (95% CI 2.0-4.2). Analysis of PK data is ongoing and will be reported. Conclusions: Alisertib can be safely administered with gemcitabine. RP2D for alisertib is 50 mg PO BID in combination with full dose gemcitabine. Best response was at least stable disease in a majority of pts with PR observed in 9% of this heavily pretreated group of patients. Most grade ≥3 TRAEs were hematologic. Results of PK studies will also be reported. Clinical trial information: NCT01924260 .

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A phase I open label study evaluating VT1021 in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.tps3158 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. TPS3158-TPS3158

Author(s):

Michael Cieslewicz ◽

Devalingam Mahalingam ◽

Wael A. Harb ◽

Amita Patnaik ◽

Joyce F. Liu ◽

...

Keyword(s):

Tumor Microenvironment ◽

Solid Tumors ◽

Dose Escalation ◽

Tumor Regression ◽

Phase 1 ◽

Human Study ◽

Statistical Hypothesis ◽

Advanced Solid Tumors ◽

Open Label ◽

Potent Inducer

TPS3158 Background: VT1021 is a cyclic pentapeptide that functions as a potent inducer of thrombospondin-1 (Tsp-1) expression in the tumor microenvironment (TME). By triggering the production of Tsp-1, VT1021 reprograms the TME from one that is immune-suppressive and tumor-promoting, to one that activates the adaptive immune system and is tumor-inhibiting. Tsp-1 reprograms the TME to: (i) induce apoptosis in tumor cells that express CD36 on their cell surface, (ii) convert macrophages from M2 to M1 polarization, which promotes phagocytosis and blunts immunosuppression and (iii) inhibit angiogenesis. Preclinical studies have shown robust anti-tumor activities of VT1021 in animal models of ovarian, pancreatic and breast cancer, including complete tumor regression and reprogramming of the immune TME. These observations led to the initiation of the first-in-human study of VT1021. Methods: This study is a first-in-human, Phase 1, open-label, multicenter, dose escalation (Part 1) study with dose expansion (Part 2) in advanced solid tumors. The primary objectives are to assess the safety and tolerability of VT1021, to assess dose-limiting toxicities (DLT), and to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). Secondary objectives include the evaluation of pharmacokinetics (PK) and pharmacodynamic (PD) effects of VT1021 in tumor and tumor microenvironment, and assessment of preliminary antitumor activity. VT1021 is administered intravenously twice weekly. DLTs will be assessed in the first cycle (Days 1-28) of the dose escalation cohort and are defined as grade 3 adverse events related to VT1021. In Part 1 of the study, 24-30 patients will be enrolled to determine the MTD and RP2D for expansion. In Part 2 of the study, 80-100 patients will be enrolled, grouped into cohorts based on disease subtypes (ovarian, pancreatic, Triple-negative breast cancers, and glioblastoma). Blood samples and biopsy samples from patients will be collected to assess PK properties and PD responses systemically as well as in the TME. No formal statistical hypothesis testing will be conducted in this study. This study is currently open for enrollment in the US. Clinical trial information: NCT03364400.

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A phase I, open-label, multicenter, first-in-human study of the safety, tolerability, pharmacokinetics, and antitumor activity of TPX-0022, a novel MET/CSF1R/SRC inhibitor, in patients with advanced solid tumors harboring genetic alterations in MET.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps3663 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS3663-TPS3663

Author(s):

David S. Hong ◽

Shiraj Sen ◽

Haeseong Park ◽

Rebecca Suk Heist ◽

Shirish M. Gadgeel ◽

...

Keyword(s):

Tumor Microenvironment ◽

Solid Tumors ◽

Dose Escalation ◽

Kinase Inhibitor ◽

Phase 1 ◽

Human Study ◽

Genetic Alterations ◽

Type I ◽

Advanced Solid Tumors ◽

Open Label

TPS3663 Background: Alterations in the MET gene, including amplifications, chromosomal translocations, and activating mutations (kinase domain [KD] or exon 14 [Δex14]), occur across various tumors and may function as oncogenic drivers. SRC family kinases function as a key downstream node for MET signaling. CSF1R is a receptor tyrosine kinase associated with tumor progression and suppression of the immune response in the tumor microenvironment. TPX-0022 is a type I kinase inhibitor with a novel macrocyclic structure that potently inhibits MET, CSF1R and SRC to simultaneously target oncogenic MET signaling, its key downstream mediators, and the tumor microenvironment. Methods: This is a multicenter phase 1 first-in-human, open-label study to determine the safety, tolerability, PK, and preliminary efficacy of TPX-0022 in adults with advanced solid tumors harboring genetic alterations in MET. TPX-0022 will be administered orally in continuous 28-day cycles. The primary endpoint is the incidence of DLTs and determination of recommended phase 2 dose (RP2D). Secondary endpoints include ORR by blinded independent central review, intra-cranial response rate, PFS and OS (dose expansion only). In the dose escalation portion, ~30 subjects age ≥18 with solid tumors harboring MET gene amplifications, Δex14, fusions or KD mutations as determined by local tissue-based or liquid biopsy will be enrolled in a 3+3 design. Intrasubject dose escalation will also be allowed. Once the RP2D has been determined, a food effect sub-study will be conducted and ~80 subjects will be enrolled in a dose expansion portion of the study into the following cohorts: I: non-small cell lung cancer (NSCLC) Δex14 (MET therapy naïve), II: NSCLC Δex14 (MET therapy pre-treated), III: MET amplified NSCLC, gastric, or hepatocellular carcinoma, IV: solid tumors with MET KD mutations or fusions. Correlative studies will include analysis of circulating cell-free DNA to identify genomic alterations that may predict activity of TPX-0022 as well as circulating protein biomarkers such as s-MET, HGF, CSF1 and serum cytokines. The study is open and enrolling in the dose escalation portion at the time of submission. Clinical trial information: NCT03993873 .

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2556 ◽

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.

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Phase 1 study to evaluate the safety and tolerability of MEDI4736 (durvalumab, DUR) + tremelimumab (TRE) in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3069 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3069-3069 ◽

Cited By ~ 9

Author(s):

Margaret K. Callahan ◽

Kunle Odunsi ◽

Mario Sznol ◽

John J. Nemunaitis ◽

Patrick Alexander Ott ◽

...

Keyword(s):

Solid Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Liver Function Tests ◽

Maximum Tolerated Dose ◽

Clinical Activity ◽

Tumor Type ◽

Open Label ◽

Expansion Phase ◽

Combination Methods

3069 Background: DUR is a human IgG1 monoclonal antibody (mAb) that blocks PD-L1. TRE is a human IgG2 mAb inhibitor of CTLA-4. Blocking these checkpoints can result in antitumor activity in some solid tumors. The targets for DUR and TRE are non-redundant, providing sound rationale for clinical testing of the combination. Methods: This is an ongoing Phase 1, multicenter, open label study (NCT01975831) with a dose escalation (3+3 design) and subsequent expansion phase. Patients (pts) with renal cell carcinoma (RCC), cervical (CC), colorectal (CRC), non-triple-negative breast (NTNBC), ovarian (OC), non-small cell lung, or head and neck cancer are eligible. Primary endpoints are safety/tolerability and identification of maximum tolerated dose (MTD) of the combination. Secondary objectives include tumor response and progression-free/overall survival. Results: As of 16 Dec 2016, 105 pts were treated. DUR 1500 mg every 4 weeks (Q4W) and TRE 75 mg Q4W X 4 was the regimen used for opening the expansion phase. Dose-limiting toxicities were reported in 4 pts: diarrhea, colitis, abnormal liver function tests (abn LFTs), and hyponatremia. The majority of treatment-related AEs (TRAEs) were Grades (Gr) 1 and 2. TRAEs ≥ Gr 3 were reported in 12 pts; the majority were diarrhea/colitis (n = 5) and abn LFTs (n = 4) and responded to established treatment algorithms. There was 1 Gr 5 TRAE: multi organ failure. No new toxicities were identified. The preliminary responses by tumor type with n ≥ 10 pts are shown in the table below. Responses were seen in OC and RCC at the Cohort 2 dose escalation level (DUR 1/TRE 3 mg/kg). There were 4 cases of SD > 24 weeks: CC, n=2; CRC, n=1; OC, n=1. PD-L1 status was not tested. Conclusions: The DUR + TRE combination has a manageable safety profile, with preliminary evidence of clinical activity. These data support continued study of the combination therapy; the study is ongoing. Clinical trial information: NCT01975831. [Table: see text]

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Surufatinib Plus Toripalimab in Patients with Advanced Solid Tumors: A Single-Arm, Open-Label, Phase 1 Trial

10.21203/rs.3.rs-125321/v1 ◽

2020 ◽

Author(s):

Yanshuo Cao ◽

Ming Lu ◽

Yu Sun ◽

Jifang Gong ◽

Jie Li ◽

...

Keyword(s):

Antitumor Activity ◽

Solid Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Fixed Dose ◽

Advanced Solid Tumors ◽

Open Label ◽

Phase 1 Trial ◽

Open Label Phase ◽

Grade 3

Abstract BackgroundPreclinical studies have supported a potential synergistic antitumor activity between surufatinib and anti-programed death ligand-1 (PD-L1). We describe here the results of a single-arm, open-label phase 1 trial to evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) in patients with advanced solid tumors treated with surufatinib combined with toripalimab, an inhibitor of PD-L1.MethodsThis is an open-label, dose escalation and expansion study in patients with solid tumors who had failed standard therapies or had no effective treatment. In the dose escalation stage, 3 cohorts of patients were treated with surufatinib, at dose levels of 200, 250, or 300 mg once daily (QD) in combination with a fixed dose of toripalimab 240 mg, every 3 weeks (Q3W), to evaluate maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Additional patients were enrolled in the dose expansion phase to further assess the efficacy, safety, and PK profile.ResultsFrom April 1, 2019 to July 10, 2020, 31 patients were screened, of which 28 patients were enrolled. One patient in the 300 mg cohort experienced dose limited toxicity (DLT), a grade 3 hyperthyroidism. The top 3 most common treatment-related adverse events of ≥ grade 3 were transaminases increased (17.9%), hypertension (14.3%) and blood bilirubin increased (10.7%). No treatment-related death or treatment discontinuation was identified. The RP2D was determined to be surufatinib 250 mg QD plus toripalimab 240 mg Q3W. Overall objective response rate was 22.2% [95% confidential interval (CI) 8.6‒42.3], and disease control rate reached 81.5% (95% CI 61.9‒93.7). ConclusionsSurufatinib plus toripalimab was well-tolerated, with no unexpected safety signals, and showed promising antitumor activity in patients with advanced solid tumors. Trial registrationclinicaltrials.gov, NCT03879057; Registered March 18, 2019, https://clinicaltrials.gov/ct2/show/NCT03879057

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Phase I dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3045 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3045-3045 ◽

Cited By ~ 1

Author(s):

Takashi Seto ◽

Taito Esaki ◽

Fumihiko Hirai ◽

Shuji Arita ◽

Kaname Nosaki ◽

...

Keyword(s):

Solid Tumors ◽

Dose Escalation ◽

Troponin T ◽

Geometric Mean ◽

Japanese Patients ◽

Advanced Solid Tumors ◽

Open Label ◽

Dose Escalation Study ◽

Primary Tumor Site ◽

Grade 3

3045 Background: AZD7762, a potent Chk1/Chk2 inhibitor, has been shown to enhance the antitumor activity of gemcitabine in xenograft models (Zabludoff SD et al. Mol Cancer Ther 2008;7:2955–66). Methods: This open-label dose-escalation study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients (pts) with advanced solid tumors (NCT00937664). Pts received AZD7762 iv alone on days 1 and 8 of a 14-day cycle (Cycle 0), followed by AZD7762 plus gemcitabine 1000 mg/m2 on days 1 and 8 of 21-day cycles, in sequential ascending AZD7762 dose cohorts. Results: 20 pts (mean age 60 years) received AZD7762 at doses of 6 (n=3), 9 (3), 21 (6), and 30 mg (8). The most common primary tumor site was lung (n=14). All pts had received ≥1 prior chemotherapy and 18 had metastatic disease. Dose-limiting toxicities (DLTs) occurred in two of six evaluable pts (both 30 mg cohort): one, grade 3 (CTCAE, v3.0) elevated troponin T (Cycle 0; AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated AST and ALT (Cycle 1; combination therapy). Thus, the 30 mg dose was regarded as non-tolerable. DLTs resolved following treatment discontinuation. The most frequently reported adverse events (AEs) in Cycle 0 (AZD7762 monotherapy) were bradycardia (50%), hypertension (25%) and fatigue (15%). Overall, the most common AEs were bradycardia (55%), neutropenia (45%), and hypertension, fatigue, and rash (30% each). AEs grade ≥3 were reported in 11 pts, the most common being neutropenia (45%) and leukopenia (25%). No pt died due to an AE. AZD7762 exposure (Cmax, AUC) increased in an approximately linear manner. Gemcitabine did not appear to affect AZD7762 PK. Arithmetic mean t½ and geometric mean CL of AZD7762 across the dose groups were 16.1–19.4 h and 22.0–32.7 L/h, respectively during the monotherapy cycle, and 15.6–18.3 h and 21.1–24.4 L/h, respectively in combination with gemcitabine. There were no objective responses; five pts (all lung cancer) had stable disease. Conclusions: The maximum tolerated dose of AZD7762 in combinationwith gemcitabine 1000 mg/m2 was determined as 21 mg in Japanese pts.

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Trials in progress: A phase 1, open-label, dose-escalation, pharmacokinetic, safety and tolerability study of the selective TAM kinase inhibitor PF-07265807 in patients with advanced or metastatic solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps2671 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS2671-TPS2671

Author(s):

Vivek Subbiah ◽

Mark M. Awad ◽

Adil Daud ◽

Martin Gutierrez ◽

Jessica Dreger McDermott ◽

...

Keyword(s):

Solid Tumors ◽

Dose Escalation ◽

Group Performance ◽

Phase 1 ◽

Objective Response ◽

Eastern Cooperative Oncology Group ◽

Human Study ◽

Open Label ◽

Measurable Disease ◽

Anti Tumor Activity

TPS2671 Background: MERTK is a receptor tyrosine kinase from the tumor-associated macrophage kinase (TAMK) family that regulates key aspects of immune homeostasis and responses to infection. MERTK inhibition may lower the threshold for immune activation thereby promoting anti-tumor activity. Agents with some degree of MERTK inhibitory activity have been investigated in the clinic, but are limited by poor potency in patients (pts) and significant off-targets effects. PF-07265807 (ARRY-067) is a selective small-molecule inhibitor of the TAMKs MERTK and AXL. In preclinical models, PF-07265807 monotherapy shows antitumor activity that results in long-term cures and resistance to tumor re-challenge when combined with anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-1/PD-L1) antibodies. This first-in-human study will evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of PF-07265807 in pts with selected advanced or metastatic solid tumors. This study will also explore the potential utility of PF-07265807 in combination with anti-PD-1/PD-L1 antibodies. Methods: This is a phase 1, open-label, multi-center, dose-escalation study (NCT04458259) to evaluate the safety, PK and tolerability of PF-07265807. Eligible participants will be adult pts with selected advanced or metastatic solid tumors who are intolerant or resistant to standard therapy. Other key eligibility criteria: measurable disease by RECIST 1.1 or non-measurable disease; Eastern Cooperative Oncology Group performance status 0–2; adequate bone marrow, renal and liver function; and resolved acute effects of any prior therapy. Successive cohorts of pts will receive escalating doses of PF-07265807 starting from 25 mg QD. Each cycle will be 21 days in duration (14 days on/7 days off). Study drug treatment will continue until disease progression or unacceptable toxicity, whichever occurs first. For dose escalation, a Bayesian logistic regression model will be used to model the relationship of dose-limiting toxicities (DLTs) to PF-07265807 dose. This model, along with escalation with overdose control, will guide the dose escalation of PF-07265807 after the completion of the DLT observation period (first two cycles of treatment, i.e. 42 days) of each cohort, until determination of the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D). After the MTD/RP2D is identified, the safety and efficacy of combined PF-07265807 and anti-PD1/PD-L1 treatment will be explored. Primary endpoints: incidence of DLTs, treatment-emergent adverse events and laboratory abnormalities. Secondary endpoints: PK parameters of PF-07265807, objective response rate and duration of response. The study began enrolling pts in September 2020 and is still recruiting. Clinical trial information: NCT04458259.

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Preliminary results from CLASSICAL-Lung, a phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2601 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2601-2601

Author(s):

Michael Rahman Shafique ◽

Terrence Lee Fisher ◽

Elizabeth E. Evans ◽

John E. Leonard ◽

Desa Rae Electa Pastore ◽

...

Keyword(s):

Clinical Trial ◽

Dose Escalation ◽

Tumor Regression ◽

Early Stage ◽

Cell Activity ◽

Open Label ◽

Expansion Phase ◽

Phase 1B ◽

Grade 3

2601 Background: Rational combination therapies are needed to overcome resistance mechanisms in NSCLC. Pepinemab is an IgG4 humanized monoclonal antibody targeting semaphorin 4D (SEMA4D, CD100). In vivo preclinical models demonstrated antibody blockade of SEMA4D promoted immune infiltration and reduced function and recruitment of immunosuppressive myeloid cells within the tumor. Importantly, preclinical combinations of anti-SEMA4D with various immunotherapies enhanced T cell activity and tumor regression. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Methods: This ongoing phase 1b/2, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 patients (pts) with advanced (stage IIIB/IV) NSCLC (NCT03268057). The trial is split into dose escalation (n = 12) and dose expansion (n = 50) phases and includes 2 cohorts; 1) pts who are immunotherapy naïve, and 2) pts whose tumors progressed during or following immunotherapy (IO failure). Pts in the dose escalation cohorts received ascending doses of pepinemab i.v. (5, 10, 20 mg/kg, Q2W) in combination with avelumab i.v. (10mg/kg, Q2W). Results: Dose escalation is complete and the RP2D was selected as 10mg/kg pepinemab, Q2W. No pts experienced a TRAE leading to study discontinuation or death. The most frequent related AEs were grades 1 or 2 fatigue, pyrexia, or chills; no grade 3 AEs occurred in more than one subject. One DLT, a grade 3 pulmonary embolism occurred in the 10mg/kg pepinemab cohort, and resolved without reoccurrence. The disease control rate for pts treated > 2 months is 90% (19/21), and, at this early stage, a PR with a 49% reduction in target lesion was observed in at least 1 of 8 pts in the IO failure cohort. Updated data from the dose expansion phase will be presented. Conclusions: Preliminary data suggest the combination is well tolerated and shows initial signals of antitumor activity. Dose escalation is complete and the expansion phase is ongoing. Clinical trial information: NCT03268057.

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Phase I dose-finding study of oral ERK1/2 inhibitor LTT462 in patients (pts) with advanced solid tumors harboring MAPK pathway alterations.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3640 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3640-3640

Author(s):

Filip Janku ◽

Elena Elez ◽

Gopa Iyer ◽

Noboru Yamamoto ◽

Daniel Shao-Weng Tan ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Drug Exposure ◽

Mapk Pathway ◽

Single Agent ◽

Human Study ◽

Clinical Activity ◽

Advanced Solid Tumors ◽

Grade 3

3640 Background: LTT462 is an investigational small molecule inhibitor of ERK1/2, which has demonstrated preclinical activity in multiple MAPK activated cancer cells and xenograft models. This first-in-human study was designed to evaluate the safety and tolerability of LTT462 in advanced solid tumors harboring MAPK pathway alterations (NCT02711345). Methods: The dose-escalation part of this Phase I, open-label study, enrolled adult and adolescent pts with advanced solid tumors harboring ≥1 documented MAPK pathway alteration with progressive disease (PD) despite standard therapy, or for whom there is no effective standard treatment. Oral LTT462 was given once daily (QD) at 45–600 mg or twice daily (BID) at 150 mg or 200 mg. Objectives were to determine the maximum tolerated dose (MTD) using a Bayesian hierarchical logistic regression model guided by escalation with overdose control, and characterize safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of LTT462. Results: Sixty-five pts (median age 60 years) including 1 pt aged 15 were enrolled in the dose-escalation; most pts (22%) had 3 prior therapies. Most common primary sites for cancer were in the colon (n = 21; 32%), ovary (n = 9; 14%), and pancreas (n = 7; 11%). All pts discontinued, the majority due to PD (n = 44; 68%). Eleven pts experienced DLTs; 6 pts experienced Grade 3 eye disorder DLTs (4 pts retinopathy, 2 pts chorioretinopathy). Treatment-related adverse events (TRAEs) were reported for 89% of pts, most commonly ( > 30%) diarrhea (n = 25; 38%) and nausea (n = 22; 34%). Grade 3/4 TRAEs were reported in 29% of pts; most common was retinopathy (n = 4; 6%). MTD of LTT462 was 400 mg QD and 150 mg BID. Overall, 8 pts (12%) had stable disease (SD) and 35 pts (54%) had PD. An unconfirmed partial response was reported in a pt with cholangiocarcinoma with BRAF mutation; best change in sum of target lesions per RECIST 1.1 was -33.9%. LTT462 increased plasma peak drug concentration and drug exposure at increasing doses between 45–450 mg QD. Exposure at LTT462 600 mg QD was lower than anticipated, indicating potential saturation of absorption at this dose. LTT462 inhibited ERK1/2 and reduced DUSP6 expression relative to baseline in most pts evaluated. Conclusions: LTT462 is well tolerated. Limited clinical activity was reported with single agent LTT462; best overall response was SD. An ongoing study is investigating LTT462 in combination with the RAF inhibitor, LXH254, in NSCLC and melanoma. Clinical trial information: NCT02711345 .

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