Phase 1b/2 SEASTAR trial: Safety, pharmacokinetics, and preliminary efficacy of the poly(ADP)-ribose polymerase (PARP) inhibitor rucaparib and angiogenesis inhibitor lucitanib in patients with advanced solid tumors.

3102 Background: Lucitanib is an oral, potent tyrosine kinase inhibitor that selectively inhibits VEGFR1–3, PDGFRα/β, and FGFR1–3. In preclinical studies, antitumor activity of rucaparib is enhanced by lucitanib through antiproliferative, antiangiogenic, and immunological mechanisms. We hypothesize that combining lucitanib and rucaparib is tolerable and can induce a higher hypoxic state and homologous recombination repair deficiency that may lead to greater sensitivity to PARP inhibition. Methods: Patients with advanced solid tumors who had ≥1 prior line of therapy were eligible. Patients with BRCA1/2-mutated ovarian cancer must have received prior PARP inhibitor. Rucaparib and lucitanib were escalated using a 3+3 phase 1b dose-escalation design from starting doses of 300 mg BID and 4 mg QD, respectively. Dose-limiting toxicities (DLTs) were assessed during the first 28 days of treatment. Plasma samples were collected for pharmacokinetic analyses. Genomic alterations were identified by local testing, or through central testing of plasma or tumor tissue. Results: As of February 1, 2021, 16 patients were treated with rucaparib + lucitanib and included in the analyses (Table). Patients had a median of 4 prior therapies; 1 patient had prior PARP inhibitor (olaparib) treatment. Median time on treatment was 58.5 days, with 2 patients ongoing as of the data cutoff date. A DLT of grade 3 proteinuria was seen in Cohort 1; no other DLTs have been reported. Across all cohorts, the most common any-grade treatment-emergent adverse events were nausea (n=9; grade ≥3, n=1), hypertension (n=8; grade ≥3, n=2) and ALT/AST increased (n=7; grade ≥3, n=3). Initial pharmacokinetic data indicated no drug interactions between the 2 agents. To date, 1 patient in Cohort 1 with PALB2-mutated advanced endometrial cancer had a confirmed partial response per RECIST v1.1, lasting 30 weeks; 6 patients had RECIST v1.1 stable disease (SD), including 1 patient each in Cohorts 1 and 3 with SD for ≥16 weeks. In addition, 1 patient in Cohort 2 with BRCA2-mutated castration-resistant prostate cancer continued to receive treatment despite initial progressing bone metastases, resulting in a prostate-specific antigen response (≥50% change) lasting 16 weeks and a best change in sum of target lesions of −46.3%. Conclusions: Initial findings suggest that rucaparib + lucitanib has an acceptable safety profile. The safety and efficacy of the combination are being further evaluated. Clinical trial information: NCT03992131. [Table: see text]

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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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A phase I dose escalation trial of ispinesib (SB-715992) administered days 1–3 of a 21-day cycle in patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.2026 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 2026-2026 ◽

Cited By ~ 7

Author(s):

E. I. Heath ◽

A. Alousi ◽

J. P. Eder ◽

M. Valdivieso ◽

L. S. Vasist ◽

...

Keyword(s):

Solid Tumors ◽

Dose Level ◽

Maximum Tolerated Dose ◽

Pharmacokinetic Data ◽

Advanced Solid Tumors ◽

Minor Response ◽

Level 3 ◽

Grade 3 ◽

Tumor Types ◽

Dose Limiting Toxicity

2026 Background: Ispinesib, a novel cytotoxic agent inhibiting the kinesin spindle protein (KSP) has demonstrated significant antitumor activity in multiple murine tumor models. The primary objectives of the study were to assess the safety and tolerability of SB-715992, to determine the dose limiting toxicity (DLT), and the maximum tolerated dose (MTD). Methods: Ispinesib was administered days 1–3 intravenously over 1 hour every 21 days, starting at a dose of 1 mg/m2/day. Traditional 3-patient cohort trial design was utilized with dose levels of 2, 4, 6, 8 mg/m2/day. Results: Twenty-seven patients (24 Caucasians, 3 African-Americans, 16 males, 11 females) with various tumor types were enrolled; colorectal (7), renal (5), bladder (2), lung (2), pharynx (2), pancreas (2), others (7). Grade 3/4 toxicities were noted starting at the 4 mg/m2 dose level with two patients developing grade 4 neutropenia; one for < 5 days, one for > 5 days (with grade 3 leukopenia). At the 6 mg/m2 dose level, grade 3 neutropenia and leukopenia were reported. At the 8 mg/m2 dose level, 3 of 3 patients had grade 4 neutropenia and leukopenia. The 6 mg/m2 dose level was declared the MTD. Toxicities seen in the additional 6 patients included grade 1 fatigue (1/6), grade 1 infusion- related flushing (1/6), grade 3 febrile neutropenia (1/6), and grade 4 neutropenia and leukopenia (1/6). The MTD cohort has been expanded to 10 evaluable patients for confirmation of tolerability and pharmacodynamic endpoints including phosphohistone 3 (PH3), cyclin E, and TUNEL assay on serial tumor biopsies. Preliminary pharmacokinetic data appear linear, but not dose proportional. As predicted, between days 1 and 3, accumulation ranged from 40 to 106%. Exposures appear comparable between cycles 1 and 2. Stable disease in 2 patients with renal cell carcinoma (4 and 5 cycles) and minor response in one patient with bladder cancer were seen. Conclusions: Treatment with ispinesib at the MTD of 6 mg/m2/day x 3 days in patients with advanced solid tumors was well tolerated with consistent dose limiting toxicity of myelosuppression. No significant financial relationships to disclose.

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Phase I dose-escalation study to evaluate the safety, pharmacokinetics, and pharmacodynamics of CEP-9722 (a PARP1-2 inhibitor) as single‑agent and in combination with temozolomide in patients with advanced solid tumors (NCT00920595).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3052 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3052-3052 ◽

Cited By ~ 6

Author(s):

Mario Campone ◽

Ruth Plummer ◽

Peter Stephens ◽

Zahir Brakchi ◽

Louiza Aissat-Daudigny ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Mononuclear Cells ◽

Excision Repair ◽

Single Agent ◽

Recommended Dose ◽

Parp Inhibition ◽

Advanced Solid Tumors ◽

Pharmacokinetics And Pharmacodynamics ◽

Grade 3

3052 Background: Poly-ADP-ribose (PAR) polymerases (PARPs) are essential in cellular processing of DNA damage via the base excision repair pathway. CEP-9722, an orally available PARP1-2 inhibitor, demonstrated single-agent antitumor activity and synergy with temozolomide (TMZ) in xenograft models. This phase I study evaluated the pharmacokinetics, pharmacodynamics, and the maximum tolerated dose (MTD) of CEP-9722 in monotherapy and combination with TMZ. Methods: Adult patients with advanced solid tumors were enrolled in cohorts of 3-6 patients to receive a 14-day cycle of CEP-9722 (days 1-5), followed by 28-day cycles of CEP-9722 (days 1-5) plus TMZ (150 mg/m2 days 1-5). The dose of CEP-9722 was 150 mg/day in the first cohort and was escalated depending on the occurrence of dose-limiting toxicities (DLTs) during cycles 1 and 2. The safety, pharmacokinetics, and pharmacodynamics (PAR levels in peripheral blood mononuclear cells) of CEP-9722 were analyzed. Results: Overall, 26 patients (18F,8 M) 18 to 71 years of age were enrolled in 5 cohorts of 3-9 patients and treated with CEP-9722 at 150-1000 mg/day. The MTD of CEP-9722 in combination with TMZ (150 mg/m2) was reached at 1000 mg/day. The recommended dose was 750 mg/day. A total of 9 patients were treated at the recommended dose. DLTs were observed in 2 patients during cycle 1 (1 grade 3 myositis at 750 mg/day and 1 grade 3 asthenia at 1000 mg/day) and 2 patients during cycle 2 (1 grade 3 asthenia at 300 mg/day and 1 persistent grade 2 weight loss at 1000 mg/day). Overall during this study, 4 grade 3 treatment-related adverse events were observed. The pharmacokinetics showed high intra- and inter-patient variability at all doses. The pharmacodynamic analysis demonstrated PARP inhibition at all doses, but the high inter- and intra-patient variability prevented any conclusion regarding a dose / PARP inhibition relationship. Conclusions: TheMTD of CEP-9722 when administered with TMZ was 1000 mg days 1-5 and the combination CEP-9722/TMZ was well tolerated. In addition, a clear signal of PARP inhibition was demonstrated.

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A phase I clinical and pharmacokinetic study of flavopiridol administered concurrently with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13515 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13515-13515

Author(s):

R. D. Meng ◽

R. D. Carvajal ◽

A. N. Tse ◽

M. A. Shah ◽

H. Dials ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Response To Treatment ◽

Fixed Dose ◽

Colorectal Cancers ◽

Pharmacokinetic Studies ◽

Pharmacokinetic Data ◽

Advanced Solid Tumors ◽

Modified Folfox6 ◽

Grade 3

13515 Background: Flavopiridol, a potent cyclin-dependent kinase inhibitor, enhances oxaliplatin-induced apoptosis in HCT116 colon cancer cells in vitro, especially with concurrent therapy. Significant tumor regressions were also observed in HCT116 xenografts treated with flavopiridol and oxaliplatin therapy versus either therapy alone. Methods: Therefore, an ongoing phase I trial in advanced solid tumors was designed in which flavopiridol at a fixed dose (40 mg/m2 over 1 hour) was administered concurrently with escalating doses of oxaliplatin (60 mg/m2 -> 80 mg/m2 over 2 hours), given as part of a modified FOLFOX6 regimen at standard doses every 14 days. Patients then received escalating doses of infusional 5-fluorouracil over 48 hours (900 mg/m2/day -> 1200 mg/m2/day). Standard phase I eligibility criteria apply. Prior FOLFOX or oxaliplatin was allowed. Results: Median characteristics of nineteen evaluable patients: age 54 (39–77), KPS 80% (70–90), 9 males/10 females, 3 prior regimens (range 1 to 10). The combination has been well-tolerated, with 1 dose limiting toxicity occurring with oxaliplatin at 85 mg/m2 and infusional 5-fluorouracil at 1200 mg/m2/day (grade 3 hyponatremia and grade 3 syncope). Pharmacokinetic studies for flavopiridol indicate no appreciable difference in Cmax despite escalation of oxaliplatin dose. We have observed 1 partial response to treatment in pancreatic cancer. Stable disease has been seen in 5 patients, including 1 breast cancer (3 months), 1 gastric cancer (2 months), 1 anal cancer (7 months) and 2 colorectal cancers (5+ months), with one patient previously treated with oxaliplatin. Conclusions: The combination of flavopiridol and modified FOLFOX6 can be given safely without a significant increase in toxicity. The pharmacokinetic data for flavopiridol remains unchanged despite escalating doses of oxaliplatin. Activity has been observed in several tumor types, with promising activity noted for colorectal cancers even with prior oxaliplatin chemotherapy. Therefore, further dose escalation of flavopiridol is currently planned. No significant financial relationships to disclose.

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Safety and pharmacokinetics of intravenous VEGF Trap plus FOLFOX4 in a combination phase I clinical trial of patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13061 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13061-13061 ◽

Cited By ~ 4

Author(s):

M. Mulay ◽

S. A. Limentani ◽

M. Carroll ◽

E. S. Furfine ◽

D. P. Cohen ◽

...

Keyword(s):

Solid Tumors ◽

Single Agent ◽

Angiogenesis Inhibitor ◽

Maximum Tolerated Dose ◽

Vegf Receptor ◽

Advanced Solid Tumors ◽

Grade 3 ◽

Ecog Ps ◽

Dose Levels ◽

Vegf Trap

13061 Background: VEGF Trap is a potent angiogenesis inhibitor comprising portions of human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (KDR) extracellular domains fused to the Fc portion of human IgG. VEGF Trap binds VEGF and neutralizes all VEGF-A isoforms plus placental growth factor. FOLFOX4 is an approved chemotherapy regimen for the treatment of colorectal cancer. This study was designed to evaluate the safety and pharmacokinetics (PK) of VEGF Trap plus FOLFOX4 administered intravenously. Methods: Successive cohorts of 3–6 patients (pts) with advanced solid tumors received intravenous VEGF Trap plus FOLFOX4 every 2 weeks. Study endpoints included safety, PK, and immunogenicity. Antitumor activity was assessed by CT scan. Results: Six pts (3 male/3 female), median age 55 (25–74), ECOG PS 0/1/2: 2/4/0, with a variety of advanced solid tumors, including 2 gastric and 2 neuroendocrine tumors, have received a total of 19 cycles of VEGF Trap plus FOLFOX4 across 2 VEGF Trap dose levels (2.0 mg/kg, 4.0 mg/kg) to date. Three of these 6 pts had grade 3 AEs (hypertension [n=2], neutropenia [n=2]), which were manageable and reversible. However, no dose-limiting toxicities or grade 4 AEs have been encountered so far. Preliminary mean free VEGF Trap clearance was 17.1 mL/kg/day. No pts have developed anti-VEGF Trap antibodies. Conclusions: VEGF Trap may be safely combined with FOLFOX4 at the dose levels studied. Preliminary free VEGF Trap clearance did not differ significantly from that seen with single-agent exposure; chemotherapy PK analysis is pending. The maximum tolerated dose has not yet been reached, and dose escalation continues. Updated safety, pharmacokinetic, and preliminary efficacy results from this ongoing study will be presented. [Table: see text]

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A phase I study of oral belinostat (PXD101) in patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14092 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14092-14092 ◽

Cited By ~ 5

Author(s):

W. K. Kelly ◽

T. Yap ◽

J. Lee ◽

U. Lassen ◽

E. Crowley ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Standard Therapy ◽

Tumor Imaging ◽

Pharmacokinetic Studies ◽

Pharmacokinetic Data ◽

Advanced Solid Tumors ◽

Grade 3

14092 Background: Belinostat (PXD101) is a hydroxamate HDAC inhibitor which demonstrates broad anti-neoplastic activity in vitro and in vivo. In Phase I studies in patients (pts) with advanced cancer, IV belinostat is well-tolerated up to 1000 mg/m2 daily x5. Preliminary results of an oral formulation of belinostat showed that the oral bioavailability was 20 - 50%. This Phase I trial of oral belinostat will determine the maximal tolerated dose (MTD) of once and twice daily dosing, tolerability and pharmacokinetics (PK) in pts with advanced solid tumors. Methods: Sequential cohorts of 3–6 pts with advanced solid tumors refractory to standard therapy or for which no standard therapy exists were administered belinostat 250–500mg once or twice daily in 4 week cycles. Fasting (day 1) and non-fasting (day 7) pharmacokinetic studies were performed on all patients along with serial ECGs to evaluate any potential effects on QTc prolongation. Patients were evaluated with routine blood work weekly and tumor imaging at the end of cycle 1 then every other cycle. Results: Sixteen pts have been treated in 3 dose levels at 250mg QD (6 pts), 500mg QD (6 pts) and 250mg BID (4 pts). The median number of cycles of therapy is 1 (range 1–5), nine pts continue to be treated. The most common reasons for discontinuation were adverse event (3 pts) and PD (3 pts). No DLTs were identified at 250mg QD or 250mg BID. DLTs of grade 3 dehydration and grade 3 fatigue were reported at 500mg QD. In pts from the first 3 dose cohorts, there were no grade 4/5 events reported. Other Grade 3 toxicities were fatigue (2 pts), abdominal pain (1 pt), ataxia (1 pt), prolonged INR (1 pt), prolonged PTT (1 pt) and confusion (1 pt). Symptoms were transient and usually resolved after drug was held. In > 500 ECG’s collected, there were no QTcF > 500 ms, and no QTcF increase > 60 ms above baseline. To date, the best clinical response observed has been SD in 7 patients. Conclusions: Oral belinostat at doses of 250mg QD and 250mg BID given on a continuous schedule appears to be well tolerated. Alternative dosing schedules are being explored to further dose escalate the belinostat. Updated safety, activity and pharmacokinetic data will be presented on these and alternate dose schedules. [Table: see text]

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423 Safety and preliminary efficacy of intratumoral cavrotolimod (AST-008), a spherical nucleic acid TLR9 agonist, in combination with pembrolizumab in patients with advanced solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0423 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A449-A449

Author(s):

Steven O’Day ◽

Cesar Perez ◽

Trisha Wise-Draper ◽

Glenn Hanna ◽

Shailender Bhatia ◽

...

Keyword(s):

Cell Carcinoma ◽

Solid Tumors ◽

San Francisco ◽

Institutional Review Boards ◽

Advanced Solid Tumors ◽

Phase 2 ◽

Serious Adverse Events ◽

Tlr9 Agonist ◽

Phase 1B ◽

Spherical Nucleic Acids

BackgroundSpherical nucleic acids (SNAs) are nanostructures consisting of radially oriented, densely packed oligonucleotides arranged in a spherical 3D architecture. SNAs have different properties than linear oligonucleotides, including increased cellular uptake, which may enhance efficacy. Cavrotolimod (AST-008) is an SNA toll-like receptor 9 (TLR9) agonist designed to robustly activate innate and adaptive immune responses. Cavrotolimod is in development for the treatment of advanced solid tumors in combination with PD-1 blockade. Prior studies demonstrated that cavrotolimod, alone and in combination with PD-1 blockade, increased circulating levels of Th1-type cytokines and activated peripheral T cells and NK cells.MethodsAST-008-102 is an ongoing Phase 1b/2 study (NCT03684785). The Phase 1b dose escalation stage examined intratumoral (IT) cavrotolimod at doses of 2, 4, 8, 16, and 32 mg in combination with pembrolizumab in patients with advanced solid tumors. Cavrotolimod was dosed once weekly for 8 weeks and once every 3 weeks thereafter. The Phase 2 dose expansion stage is examining cavrotolimod 32 mg IT in combination with IV pembrolizumab for the treatment of advanced Merkel cell carcinoma (MCC) and in combination with IV cemiplimab for the treatment of advanced cutaneous squamous cell carcinoma (CSCC). Both cohorts are enrolling patients with documented progression of disease on PD-(L)1 blockade. This analysis provides interim results of the Phase 1b stage.ResultsIn the Phase 1b stage, 20 patients were enrolled across all planned dose levels. No dose-limiting toxicities, grade (G)4 toxicities, or treatment-related serious adverse events (AEs) were observed. The most common AEs were injection site reactions (ISRs) and flu-like symptoms. All treatment-related AEs were < G3 except agitation and ISR (1 each). At data cutoff, ORR is 21% (4 of 19 evaluable patients) in a heterogeneous population with solid tumors. All 4 responders (2 melanoma and 2 MCC patients) have ongoing responses, with duration of response exceeding 52 weeks in 2 patients. Three of 4 responders had disease progression on PD-1 blockade at the time of enrollment, and one patient had a prior response to PD-1 blockade, but subsequently relapsed off therapy. Regression of both injected and noninjected lesions was observed. Gene expression analyses demonstrated increased IT infiltration by cytotoxic immune cells in both injected and noninjected tumors. The highest dose (32 mg) was selected for the Phase 2 stage.ConclusionsIT administration of cavrotolimod appears to be safe and well tolerated in combination with pembrolizumab. Durable responses have occurred in patients previously experiencing progressive disease on PD-1 blockade.Trial RegistrationNCT03684785Ethics ApprovalThe study was approved by Institutional Review Boards of Dana-Farber Cancer Institute (IRB #18-584), John Wayne Cancer Institute (WIRB #20183064), University of Miami (IRB #20180957), University of Iowa (IRB #201810763), University of Cincinnati (WIRB #20183064), University of Washington (WIRB #20183064), MSKCC (IRB #20-174), UC San Francisco (WIRB #20183064), U Colorado (WIRB #20183064), Northwestern (IRB #STU00211083), U Arizona (WIRB #20183064), UC Irvine (WIRB #20183064), U Pitt (WIRB #20183064), and Washington University (WIRB #20183064).

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287 Safety and antitumor activity of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor KHK2455 in combination with anti-CCR4 monoclonal antibody mogamulizumab in patients with advanced solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0287 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A313-A314

Author(s):

Solmaz Sahebjam ◽

Jameel Muzaffar ◽

Timothy Yap ◽

David Hong ◽

Olivier Rixe ◽

...

Keyword(s):

Monoclonal Antibody ◽

Overall Survival ◽

Antitumor Activity ◽

Combination Therapy ◽

Adverse Events ◽

Solid Tumors ◽

Ex Vivo ◽

Advanced Solid Tumors ◽

Grade 3 ◽

Dose Dependent

BackgroundIDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Mogamulizumab is an anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody that has shown synergy with KHK2455 in preclinical models. Mogamulizumab is approved in the US and EU for treatment of mycosis fungoides and Sézary syndrome.MethodsIn this first-in-human study, patients with advanced solid tumors received escalating oral doses of KHK2455 alone (0.3, 1, 3, 10, 30 and 100 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV mogamulizumab for 4 weeks (Cycle 1), and then on Days 1 and 15 (from Cycle 2 onward) in a standard 3+3 Phase I design. Safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production) were evaluated.ResultsThirty-six patients were enrolled across all cohorts. One patient with lower esophageal cancer in the 100 mg cohort exhibited dose-limiting toxicity (Grade 3 gastrointestinal necrosis). The most frequent (≥10%) treatment-emergent adverse events (TEAEs) are presented in table 1. Overall numbers of TEAEs, ≥Grade 3 TEAEs, and serious TEAEs related to KHK2455 and mogamulizumab are presented in table 2. Serious KHK2455-related TEAEs included gastrointestinal necrosis (KHK2455 monotherapy), and nausea and drug eruption (combination therapy). In addition, five drug-related TEAEs in combination therapy led to discontinuation; there were no fatal outcomes related to either study drug. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated by plasma Kyn concentration and Kyn/Trp ratio (median inhibition 70.5% and 70.8%, respectively, at 100 mg dose on Day 15, compared to baseline) and ex vivo Kyn production (>95% inhibition at ≥10 mg KHK2455), confirming target modulation. Six of 26 evaluable patients from all dosing groups achieved durable disease stabilization (≥6 months, RECIST 1.1), and one patient with bevacizumab-resistant glioblastoma demonstrated confirmed partial response (43.5% tumor reduction over a 2-year observation period). Median overall survival was 13.4 months, with 30% of subjects surviving for 2 years or longer (figure 1).Abstract 287 Table 1Study 2455-001: Treatment-Emergent Adverse Events (≥10% by Preferred Term)Abstract 287 Table 2Abstract 287 Figure 1Study 2455-001: Overall SurvivalConclusionsKHK2455 in combination with mogamulizumab was well-tolerated and manageable at all doses tested, suppressed Kyn production in a dose-dependent and sustained manner, and demonstrated signals of antitumor activity. These data support the continued development of this combination.AcknowledgementsMedical writing assistance was provided by Susan E. Johnson, PhD, S.E. Johnson Consulting, LLC, New Hope, PA, USA.Trial RegistrationNCT02867007 (www.clinicaltrials.gov)Ethics ApprovalThis study was approved by Ethics Committees at all participating study institutions.

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Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001095 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001095 ◽

Cited By ~ 1

Author(s):

Lillian Siu ◽

Joshua Brody ◽

Shilpa Gupta ◽

Aurélien Marabelle ◽

Antonio Jimeno ◽

...

Keyword(s):

Radiation Therapy ◽

Solid Tumors ◽

Phase 1 ◽

Objective Response ◽

Clinical Activity ◽

Advanced Solid Tumors ◽

Palliative Radiation ◽

Cell Counts ◽

Palliative Radiation Therapy ◽

Grade 3

BackgroundMEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.Patients and methodsEligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.ResultsFrom November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.ConclusionIT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.Trial registration numberNCT02556463.

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