A phase 1, multicenter, dose-escalation study of PRN1371, an irreversible covalent FGFR1-4 kinase inhibitor, in patients with advanced solid tumors, followed by expansion cohorts in patients with FGFR genetic alterations.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2616-TPS2616 ◽  
Author(s):  
Sarina Anne Piha-Paul ◽  
Cinta Hierro ◽  
Valentina Boni ◽  
Victor Moreno ◽  
Noah M. Hahn ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Phase 1 ◽  
Elevated Serum ◽  
Genetic Alterations ◽  
Serum Phosphorus ◽  
Advanced Solid Tumors ◽  
Phosphate Binding ◽  
Pharmacodynamic Biomarkers ◽  
Fgfr Inhibition

TPS2616 Background: FGFR inhibition is a promising and clinically proven therapeutic approach in a number of solid tumors where genetic alterations of FGFR drive oncogenesis. PRN1371 is a highly selective oral, irreversible inhibitor of FGFR1-4 that exhibits high potency in cancer cell lines harboring FGFR alterations, including mutations and fusions. Methods: Part A of this phase 1 clinical trial explores ascending doses of PRN1371 in adult patients with advanced solid tumors in a "3 + 3" design, where cohorts of three patients are studied at each level until additional patients need to be added to better assess safety, establish the maximum tolerated dose and define the recommended phase 2 dose (RP2D). PRN1371 is dosed once or twice daily in continuous, 28-day cycles until disease progression. Part B studies include two or three expansion cohorts of different tumor types, 10 patients each with FGFR1-4 gene mutations, fusions, or amplification at the RP2D. The on-target effect of serum phosphorus and FGF23 increases are measured as potential pharmacodynamic biomarkers. Elevated serum phosphorus is managed with oral phosphate binding medications and a low phosphate diet, with dose interruptions and use of acetazolamide if certain thresholds are exceeded. Circulating tumor DNA from patients at baseline and during follow up is analyzed for FGFR genetic alterations. Pre and on-treatment tumor biopsies in Part B will be tested for a panel of pharmacodynamic biomarkers of FGFR inhibition. Clinical trial information: NCT02608125.

Trial in progress: A phase 1-2 multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABN401 in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3157-TPS3157
Author(s):  
Dae Ho Lee ◽  
Aflah Roohullah ◽  
Byoung Chul Cho ◽  
Charlotte Rose Lemech ◽  
Paul L. de Souza ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Locally Advanced ◽  
Local Therapy ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Open Label

TPS3157 Background: c-MET (hepatocyte growth factor (HGF) receptor) overexpression, either by gene amplification, or mutation is associated with oncogenic transformation in numerous malignancies including lung, gastric, skin, renal, colorectal, and pancreatic cancers. ABN401 inhibits the activation of c-MET by reversibly interfering with the binding of c-Met tyrosine kinase to adenosine triphosphate (ATP) and blocking the receptor's downstream signaling that has demonstrated efficacy in NSCLC and gastric cancer in mouse xenograft and PDx models. This clinical trial is in progress in patients with advanced cancers. Methods: ABN401 is being evaluated in an open-label, non-randomized, dose-escalation (phase 1) study in patients with advanced solid tumors, and dose-expansion (phase 2) in patients with targeted indications and c-MET biomarker expression (NCT04052971). The phase 1 explores ascending daily doses of oral ABN401 monotherapy in 21-day cycles to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). A preplanned extension (pilot expansion) study has been initiated based on predefined positive efficacy signals at intermediate doses up to 10 NSCLC patients who have c-MET alteration. Once RP2D is determined, the phase 2 expansion of up to 10-29 patients in four specific tumor-type cohorts is planned, utilizing a Simon's optimal two-stage design to evaluate the clinical activity of ABN401. ABN401-001 study began enrolling patients in August 2019 and is ongoing in Korean and Australia. Dose escalation up to cohort 4 has been completed, enrollment to cohort 5 began in November 2020. AEs are assessed according to CTCAE v5. Tumor response is determined according to RECIST 1.1 criteria and safety findings reviewed by the DRC, which will determine the RP2D and MTD. Key Phase 1 eligibility criteria include 1) histological or cytological diagnosis of melanoma or any type of carcinoma or sarcoma and 2) refractory metastatic disease, or refractory locally advanced disease not amenable to local therapy. For the extension (pilot expansion) study, patients must have NSCLC with MET exon 14 skipping, MET amplification and/or c-MET overexpression. An exploratory study is being conducted for co-development of a companion diagnostic (CDx) system including a CTC device and ddPCR kit through liquid biopsy. Clinical trial information: NCT04052971.

First-in-human biomarker-driven phase I trial of the potent and selective glutaminase-1 (GLS1) inhibitor IACS-6274 (IPN60090) in patients (pts) with molecularly selected advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3001-3001
Author(s):  
Timothy A. Yap ◽  
Ecaterina Elena Dumbrava ◽  
Jordi Rodon Ahnert ◽  
David S. Hong ◽  
Shubham Pant ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Biologically Active ◽  
Glutamine Metabolism ◽  
Cancer Center ◽  
Advanced Solid Tumors ◽  
Preclinical Models

3001 Background: Glutamine metabolism is frequently deregulated in different cancers, including tumors harboring KEAP1/ NFE2L2 mutations or those expressing low Asparagine Synthetase (ASNS) levels. IACS-6274 is a potent oral GLS1 inhibitor discovered at MD Anderson Cancer Center with excellent pharmacokinetics (PK) and antitumor activity in biomarker-defined preclinical models. Methods: Pts with advanced solid tumors received IACS-6274 BID at escalating doses using a phase 1 BOIN design. PK and pharmacodynamic (PD) studies were conducted in serial tumor and/or blood samples. Peripheral glutamine metabolism was assessed in peripheral blood mononuclear cells (PBMC) to assess glutamine metabolism via 13C-isotope labelling. Predictive biomarker studies included tumor analyses for KEAP1, NFE2L2, STK11, NF1 mutations and IHC for ASNS loss. Results: 22 pts with advanced ovarian (n=8), NSCLC (n=7), melanoma (n=2), leiomyosarcoma, gastric, anal, endometrial and HNSCC (all n=1) received IACS-6274 at 20 (n=1), 40 (n=1), 80 (n=1), 120 (n=4), 180 (n=11) or 240 (n=4) mg BID. Molecular alterations assessed included pts with ASNS loss (n=6), STK11 (n=5), KEAP1 (n=5), NFE2L2 (n=4) and NF1 (n=1). Prior lines of therapies: 2-4 (n=12); ≥5 (n=10). Common IACS-6274-related adverse events included G1-2 photopsia (n=7), photophobia (n=7), increased creatinine (n=4) and AST (n=4). Less common G3 toxicities at 180 and 240 mg included reversible nausea (n=3), vomiting and fatigue (n=2). Dose-limiting toxicities of G3 acute renal failure and PRES syndrome were seen in one patient at 240mg BID, which fully resolved. Plasma exposures showed a dose-dependent increase across doses with observed half-life ̃12 hrs. Patients at 180mg displayed steady-state exposures at C1D14 with Cmax of 45.8 μM +/- 18.6 μM and average AUC(0-12hrs) of 382.48 h*μM +/- 159.27 h*μM. Glutamate to glutamine ratios decreased in PBMC samples in pts at C1D14 vs baseline; pts at 120, 180 and 240 mg had inhibition of 82.5% (P<0.0001), 83.9% (P<0.0001) and 85.3% (P<0.0001), respectively, exceeding doses predicted to be efficacious in preclinical models. A robust PK/PD relationship was established across doses (P<0.0001). The recommended phase 2 dose was 180mg BID. Best RECISTv1.1 response was stable disease (SD) in 17 of 20 evaluable pts. Disease control rate at 12 weeks was 60%. Durable RECISTv1.1 SD ≥6 months +/- tumor regression were seen in pts with advanced ASNS-loss ovarian cancer (n=2), PD-1/L1-exposed melanoma (n=2) and NF1 mutant leiomyosarcoma (n=1). Conclusions: IACS-6274 was well tolerated at biologically active doses with good human PK, significant PD target modulation and preliminary antitumor activity observed. The clinical trial assessment of rational combinations to maximize benefit in molecularly-selected pts is initiating. Clinical trial information: NCT03894540.

Phase I study investigating the safety of stereotactic body radiotherapy (SBRT) with anti-PD-1 and anti-IL-8 for the treatment of multiple metastases in advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2681-TPS2681
Author(s):  
Lilit Karapetyan ◽  
Adam C. Olson ◽  
William E. Gooding ◽  
Riyue Bao ◽  
Steven J. Chmura ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Suppressor Cells ◽  
Neutralizing Antibody ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Multiple Metastases ◽  
Organ Site

TPS2681 Background: Anti-PD-(L)1 immunotherapy improves outcomes for patients across various cancers; however, many patients do not benefit. Previous studies combining multi-site SBRT with anti-PD1 have confirmed feasibility and revealed induction of interferon signaling by SBRT. Elevated levels of serum IL8 (sIL8) associate with lack of response to anti-PD1 and we have observed that elevated IL8 is strongly associated with lack of response to immunotherapy and SBRT combinations. Overcoming IL8 induced epithelial-mesenchymal transitioning and trafficking of myeloid derived suppressor cells in tumor microenvironment therefore represents a promising strategy to overcome resistance. BMS-986253 is a fully human neutralizing antibody that binds to sIL8. The combination of BMS-986253 and nivolumab was safe in patients with advanced solid tumors. The present study aims to evaluate safety and preliminary efficacy of combining BMS-986253 with nivolumab and SBRT in patients with advanced solid tumors, Melanoma (MEL) and Renal Cell Carcinoma (RCC). Methods: This is a phase 1 open label single arm study (CT.gov: NCT04572451) which will include safety and efficacy cohorts. Patients will receive SBRT in 1-4 tumor lesions, in 3 or 5 fractions, at the total of 30 or 45 or 50 Gy based on the irradiated organ site. This will be followed by intravenous (IV) nivolumab (480mg q4 weeks (W)) and IV BMS-986253 (2400mg q2W) within seven days of completing SBRT. In the initial safety portion of the clinical trial, we will include 30 patients with advanced/metastatic solid tumors in order to evaluate safety. The primary endpoint of dose limiting toxicity will be assessed by continual Bayesian monitoring. The toxicities will be attributed to combination of SBRT/Immunotherapy as opposed to individual components. The secondary objective of the study is efficacy with an endpoint of objective response rate (ORR) as assessed by RECIST v1.1 in Mel and RCC. We will include 20 patients with MEL and RCC and compare against a historical benchmark of 20% ORR as sufficient signal of activity for further study. ORR will be assessed for association with serum IL-8 levels and radiation-induced changes in peripheral blood T cell populations. Clinical trial information: NCT04572451.

Phase I dose escalation of KD033, a PDL1-IL15 bispecific molecule, in advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2568-2568
Author(s):  
Jason J. Luke ◽  
Anthony J. Olszanski ◽  
Igor Puzanov ◽  
Dan Lu ◽  
Adrian Hackett ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Cell Activation ◽  
Nk Cell ◽  
Phase 1 ◽  
Locally Advanced ◽  
Advanced Solid Tumors ◽  
Efficacy Evaluation ◽  
Open Label

2568 Background: IL-2 and IL-15 signal through the shared IL-2/15 βγ receptor, but unlike IL-2, IL-15 does not expand regulatory T cells (Tregs), does not mediate activation-induced cell death and may have an improved therapeutic index. KD033 is a fusion antibody combining a fully human, high affinity anti-human Programmed Death Ligand 1 (PD-L1) IgG1 antibody with the human IL-15 receptor alpha (IL15Rα) sushi domain and human IL-15 (IL-15). KD033 (or its mouse cross reactive surrogate molecule, srKD033) has been extensively characterized in multiple in vitro and in vivo nonclinical studies. The fusion of anti-PD-L1 antibody to IL-15 significantly increases the maximal-tolerated dose (MTD) of srKD033 in mice compared to free IL-15. In addition, srKD033 has exhibited increased efficacy in rejecting tumors in mice as compared to the combination of its individual components, anti-PD-L1 antibody and IL-15. Methods: This is a phase 1, open-label, multiple ascending dose, multi-center clinical trial being conducted in patients with metastatic or locally advanced solid tumors (NCT04242147). The primary objective is to determine the safety and tolerability and the MTD of KD033. Secondary objectives include characterization of PK and immunogenicity, evaluation of CD8 T and NK cell activation and assessment of best overall response and duration of response. KD033 is administered by IV infusion over 30 minutes every 14 days. Accelerated intra-patient dose escalation across the initial three dose levels, followed by 3+3 escalation thereafter, is investigating dose ranges from 3 µg/kg to 600 µg/kg. Efficacy evaluation is planned in an expansion cohort of patients with PD-1/L1 refractory tumors. Results: A total of 7 patients have received treatment. Three patients were dosed in Cohort 1 and four patients were dosed in Cohort 2. Through two dose escalation cohorts (3 µg/kg – 25 µg/kg), no dose-limiting toxicities have been reported. Grade 1-2 treatment-related toxicities, when observed, resolved within 24 hours with supportive management. 6 patients are evaluable for treatment response with one patient (adenoid cystic carcinoma) in the first cohort having stable disease for more than 6 months. Conclusions: KD033 has been well tolerated early in dose escalation with on-mechanism pharmacodynamics consistent with IL-15 agonism. Clinical trial information: NCT04242147.

Phase 1 dose-escalation study of ACT001 in patients with recurrent glioblastoma and other advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2037-2037
Author(s):  
Jason D. Lickliter ◽  
Ross Jennens ◽  
Charlotte Rose Lemech ◽  
Ganessan Kichenadasse ◽  
Dongpo Cai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Radiation Treatment ◽  
Phase 1 ◽  
Dose Range ◽  
Malignant Gliomas ◽  
Advanced Solid Tumors ◽  
Biomarker Analysis ◽  
Dose Levels

2037 Background: ACT001, an orally-available parthenolide derivative targeting NF-κB and STAT3 signaling pathways, has immunomodulatory effects and showed promising activity in preclinical models of glioblastoma (GBM). The updated data in this report summarizes clinical findings from this first-in-human clinical trial of ACT001 in patients with advanced solid tumors, including GBM. Methods: Eligible patients were adults with ECOG PS 0-1 and satisfactory hematologic, renal and hepatic function. Additionally, GBM patients had progressive disease despite initial radiation and temozolomide, measurable tumor and no radiation treatment within 3 months prior to enrollment. ACT001 was given orally BID until intolerance or disease progression. Dose escalation followed a standard 3+3 design. Gliomas were imaged with MRI every 8 weeks and responses assessed using RANO criteria. Results: A total of 24 patients were enrolled as of this report: 14 with primary GBM, 2 with secondary GBM, 2 with anaplastic astrocytoma, 2 with colorectal cancer and 1 with each of anaplastic oligioastrocytoma, diffuse intrinsic pontine glioma, non-small cell lung cancer and pleural epithelioid mesothelioma. Median age was 49 years old (range 32-72). ACT001 dose levels were 100 mg BID, 200 mg BID, 400 mg BID, 600 mg BID, 900 mg BID and 1200 mg BID. Study drug treatment was well tolerated with no dose-limiting toxicity or ACT001-related SAE observed. The originally-planned maximum dose of 600 mg BID and the 1200 mg BID dose were expanded to 7 and 5 patients, respectively. The plasma half life of ACT001 was approximately 3-4 hours and no accumulation was observed after multiple dosing. Cmax and AUC0-last were approximately dose linear across the evaluated dose range. Of the 19 patients with recurrent malignant gliomas, a complete remission was observed in 1 patient with GBM (ongoing 27 months from starting ACT001) and stable disease lasting ≥ 6 months was seen in 3 patients. Preliminary biomarker analysis of PBMC samples revealed a post-treatment reduction in CD4+ Treg cells at some dose levels. Conclusions: In this first-in-human phase 1 study, ACT001 was well tolerated and showed satisfactory bioavailability and preliminary evidence of anti-tumor activity in malignant glioma patients dosed at 400 mg BID or lower. A phase 1b trial in recurrent GBM patients of ACT001 at 200-400 mg BID in combination with anti-PD-1 therapy is planned. Clinical trial information: ACTRN12616000228482.

Phase 1/2a study of double immune suppression blockade by combining a CSF1R inhibitor (pexidartinib/PLX3397) with an anti PD-1 antibody (pembrolizumab) to treat advanced melanoma and other solid tumors.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS465-TPS465 ◽  
Author(s):  
Zev A. Wainberg ◽  
Peter D. Eisenberg ◽  
Jasgit C. Sachdev ◽  
Amy M. Weise ◽  
David Ross Kaufman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Phase 1 ◽  
Normal Function ◽  
Clinical Activity ◽  
Ratio Test ◽  
Advanced Solid Tumors ◽  
Tumor Resistance ◽  
Open Label ◽  
Activated T Cells

TPS465 Background: Tumor-associated macrophages (TAMs) support tumor growth and cause tumor resistance to chemotherapy and radiation therapy; myeloid-derived suppressor cells (MDSCs) suppress anti-tumor immunity and cause resistance to PD-1 inhibition. TAMs and MDSCs are both regulated by colony stimulating factor 1 (CSF1). Pexidartinib is a small molecule inhibitor of CSF1 receptor, CSF1R. The normal function of PD-1, expressed on the cell surface of activated T-cells, is to suppress excessive immune responses, eg, autoimmune reactions. Tumors utilize PD-1 signaling to downregulate immune-mediated elimination. Pembrolizumab is a potent, highly selective humanized monoclonal antibody that blocks interactions between PD-1 and its ligands, PD-L1 and PD-L2. We present the study design for a Phase 1/2a clinical trial assessing safety, efficacy, pharmacokinetics, and pharmacodynamics of the combination of pexidartinib and pembrolizumab in advanced solid tumors (NCT02452424). Methods: In Part 1 of this open-label, uncontrolled trial, patients with advanced solid tumors will receive pembrolizumab (200 mg IV q 3 weeks) and escalating daily oral doses of pexidartinib to establish the safety and tolerability of the combination and a recommended phase 2 dose (RP2D). In Part 2, the combination RP2D will be studied in an expanded panel of solid tumor cohorts in up to 475 patients, to assess safety and preliminary efficacy. The panel will include GI malignancies for which preclinical data support this combination, including gastric and gastro-esophageal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, and GI stromal tumors. Overall response rate (RECISTv1.1) and progression free survival will be evaluated. Exploratory endpoints include novel biomarkers of clinical activity and drug mechanisms of action. A truncated sequential probability ratio test will be employed in each tumor cohort to allow early decision-making for futility or success. The results will support further development of the pexidartinib/pembrolizumab combination in the solid tumors that respond to treatment in this study. Clinical trial information: NCT02452424.

Final results from the phase I study expansion cohort of the selective FGFR inhibitor Debio 1,347 in patients with solid tumors harboring an FGFR gene fusion.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3603-3603
Author(s):  
James M. Cleary ◽  
Gopa Iyer ◽  
Do-Youn Oh ◽  
Ingo K. Mellinghoff ◽  
Lipika Goyal ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Colon Cancer ◽  
Solid Tumors ◽  
Gene Fusion ◽  
Phase 1 ◽  
Lung Neoplasm ◽  
Advanced Solid Tumors ◽  
Blurred Vision

3603 Background: Debio 1347 is a selective oral inhibitor of FGFR 1-3 tyrosine kinases. It exhibited high antitumor activity in in vitro and in vivo tumor models with FGFR1-3 gene fusions. Here we report the results of the expansion portion of a Phase 1 study of advanced solid tumors patients (pts) harboring an FGFR1-3 gene fusion. Methods: Pts with advanced refractory solid tumors harboring an FGFR1-3 gene fusion were enrolled. Based on results from the dose escalation portion, pts received Debio1347 80 mg once daily (qd) in 28-day cycles. Pharmacokinetics (PK) and pharmacodynamics were evaluated. The data cut-off was October 8, 2019. Results: Among 18 pts enrolled, 5 had primary brain tumors (PBT), 5 had cholangiocarcinoma, 2 had urothelial cancer, 2 had colon cancer, 1 patient each lung neoplasm, gastric cancer, endometrial cancer and squamous cell carcinoma of the chest wall. Tumors harbored fusions with FGFR1 (n = 1), FGFR2 (n = 8), and FGFR3 (n = 9). All had prior systemic therapy (median 3 lines; range 1-4). The most common treatment emergent adverse events were fatigue (50%), hyperphosphatemia (44.4%), anemia (38.9%), alopecia (33.3%), nausea (33.3%), vomiting (33.3%), constipation (33.3%), and palmar-plantar erythrodysesthesia syndrome (22.2%). Blurred vision was reported in 1 pt. There were no findings on ocular exams compatible with retinal detachment. No grade 3 AE related to study drug were reported. One patient needed dose reduction due to grade 2 nails toxicity. In PK analysis, plasma steady-state was rapidly achieved and serum phosphate increase correlated with Debio 1347 plasma exposure, confirming target engagement at 80 mg qd. Median follow-up was 18 weeks. Partial responses were observed in 3 pts harboring an FGFR2 fusion: 1 out of 2 colon cancer and 2 out 5 cholangiocarcinoma. Median duration of response was 16.1 weeks (range: 8.4-22.8+). Overall disease control was observed in 11 out of 14 pts without PBT (79%). Median PFS was 18.3 weeks. No signs of activity were observed in the 5 patients with PBT, all with an FGFR3-TACC3 fusion. Conclusions: Debio 1347 at the recommended dose of 80 mg qd was generally well tolerated and showed signs of activity in solid tumors harboring an FGFR fusion. The FUZE phase 2 clinical trial of Debio 1347 is recruiting FGFR fusion-positive advanced solid tumors irrespectively of tumor histology, excluding PBT. Clinical trial information: NCT01948297 .

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