An open-label, dose escalation, safety, and pharmacokinetic study of ENMD-2076 administered orally to patients with advanced cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3520-3520 ◽  
Author(s):  
B. R. Bastos ◽  
J. Diamond ◽  
R. Hansen ◽  
D. Gustafson ◽  
J. Arnott ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Dose Escalation ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Performance Status ◽  
Preliminary Evidence ◽  
Open Label ◽  
Once Daily ◽  
Number Of Treatment

3520 Background: ENMD-2076, a novel, orally-active antimitotic and antiangiogenic molecule inhibits Aurora A as well as tyrosine kinases that drive tumor vascularization, including VEGFR2 (KDR), PDGFR and the FGF receptors. This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of ENMD-2076 administered once daily to patients (pts) with advanced cancer. Methods: The dose escalation scheme utilizes 3 (or 4) + 3 (or 2) design. Pts receive ENMD-2076 once daily in 28-day cycles (followed by 7–14 days of rest between cycles 1 and cycle 2 only). Results: 14 pts have been enrolled in 3 dose cohorts (range 60 to 120 mg/m2/d). Median age/performance status is 62/1. The total number of treatment cycles to date is 45, with a median of 3 cycles (range <1 to 9 cycles). Most frequent, related toxicities (all grades, n=14) were hypertension (29%), fatigue (21%), proteinuria and diarrhea (both 14%). One pt experienced dose limiting toxicity of Grade 4 hypertension and Grade 3 cholecystitis in the first dose cohort of 60 mg/m2/d. Following drug interruption, the pt restarted at 30 mg/m2/d and continued for 4 additional cycles before being removed for progressive disease. Noncompartmental PK analysis of the first two dose levels shows that the plasma concentration of ENMD-981693 (the active free base of ENMD-2076) is dose- linear, as reflected in AUC and Cmax. The estimated terminal half-life (t1/2) is unaltered regardless of dose; however, t1/2 is approximately 50% greater at steady state than following single dose administration. Four ovarian cancer and 2 colon cancer pts have achieved decreases ranging from 11–61% in either CA125 or CEA, respectively (4 are associated with stable disease at Cycle 2 by modified RECIST criteria). Serum KDR concentrations assayed by ELISA decreased from baseline in all patients on treatment from a mean of 9153 pg/mL (SEM 464.2) at D1 to 6987 pg/mL (SEM 460.0) at D28 (p <0.05). Conclusions: ENMD-2076 is a small molecule kinase inhibitor with acceptable toxicity and preliminary evidence of antitumor activity in pts with ovarian and colorectal cancers. [Table: see text]

A single-center, open-label, dose escalation, safety, and pharmacokinetic study of ENMD-1198 administered orally to patients (pts) with advanced cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3562-3562
Author(s):  
S. Nallapareddy ◽  
D. Gustafson ◽  
S. Leong ◽  
W. Messersmith ◽  
J. Arnott ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Dose Escalation ◽  
Drug Exposure ◽  
Phase 1 ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Significant Treatment ◽  
Elimination Half ◽  
Label Dose

3562 Background: ENMD-1198 (2-methoxyestra-1, 3, 5, (10) 16-tetraene-3-carboxamide), an analog of 2-methoxyestradiol (2ME2), has both antiangiogenic and antiproliferative effects in various tumor types. ENMD-1198 inhibits MT polymerization by binding to β-tubulin at the colchicine-binding site and inhibits HIF-1alpha. This Phase 1 study is evaluating the safety of ENMD-1198 to determine the maximum tolerated dose. Methods: Eligible pts had advanced cancer for which no effective therapy exists that is either evaluable by RECIST criteria or tumor markers that could be monitored for clinical benefit. Phase 1 dose escalation in 3+3 design for first 5 cohorts; modified to 1 pt cohorts for subsequent cohorts until Grade 2 treatment related toxicity, and then standard 3+3 design. All pts treated with once daily oral ENMD-1198 in 28-day cycles (with post-treatment drug-free observation period of 7–14 days in Cycle 1 only). Pts are treated until the appearance of significant treatment-emergent toxicities or disease progression (PD) occurs. Results: To date, 27 pts have been enrolled in 12 dose cohorts (range 5 to 550 mg/m2/d). Median age/performance status is 61/1. Total # of treatment cycles to date is 68, with a median of 2 cycles (range <1 to 15 cycles). Most frequent toxicities (all grades, n=22) were pain (77%), fatigue (55%), constipation (36%), neuropathy and nausea (both 32%), and anemia (27%). 4 pts have experienced stable disease (SD) for more than 2 cycles. There have been no objective responses to date. 2 pts experienced dose limiting toxicity with Grade 4 neutropenia in the 550 mg/m2/d cohort. Following drug holiday, pts restarted at 425 mg/m2/d and continued for at least 1–2 more cycles before being removed from study for PD. One pt (neuroendocrine ca pancreas) is experiencing prolonged SD at 60 mg/m2/d >14 cycles and a 2nd pt (prostate ca) experienced SD at 30mg/m2/d for 10 cycles. ENMD-1198 was absorbed rapidly after oral administration. There was a linear relationship between dose and drug exposure as measured by AUC across all doses (5 - 550 mg/m2). The elimination half-life of ENMD- 1198 averaged more than 12 hours after a single dose. Conclusions: DLT was identified at 550 mg/m2/d. Cohort expansion at 425mg/m2/d is ongoing. [Table: see text]

Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1540-1540 ◽  
Author(s):  
Sheeba K. Thomas ◽  
Wael A. Harb ◽  
Joseph Thaddeus Beck ◽  
Gabrail Nashat ◽  
M. Lia Palomba ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Open Label ◽  
Label Dose ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

Abstract Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation. Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006). Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented. Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. Disclosures Thomas: Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.

scholarly journals Erratum to: A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral foretinib, a multi-kinase inhibitor, in patients with solid tumors

2015 ◽  
Vol 33 (6) ◽  
pp. 1292-1292 ◽  
Author(s):  
Geoffrey I. Shapiro ◽  
Stewart McCallum ◽  
Laurel M. Adams ◽  
Laurie Sherman ◽  
Steve Weller ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Dose Escalation Study ◽  
Once Daily

Escalation portion of phase II study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K/mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2550-2550
Author(s):  
Patrick Y. Wen ◽  
John Frederick De Groot ◽  
James D. Battiste ◽  
Samuel Aaron Goldlust ◽  
James Stuart Garner ◽  
...  
Keyword(s):  
Oral Mucositis ◽  
Dose Escalation ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Current Phase ◽  
Clinical Activity ◽  
High Grade ◽  
Newly Diagnosed ◽  
Open Label ◽  
Once Daily

2550 Background: Paxalisib (previously GDC-0084) is a potent, oral, selective, brain-penetrant, small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin. The PI3K pathway is upregulated in ~85% of GBM cases and paxalisib has shown efficacy in preclinical models. A phase I study (NCT01547546) investigated paxalisib dosed once daily in 47 patients with recurrent high-grade gliomas and established a maximum tolerated dose (MTD) of 45mg once daily. The current phase Il study aims to explore the safety, tolerability, and clinical activity of paxalisib in newly diagnosed GBM and an unmethylated MGMT promotor following surgery and temozolomide chemoradiation per Stupp regimen. Methods: Part 1 of this study is an open-label, dose-escalation phase to assess the safety, tolerability and MTD. Dose-escalation started at 60mg and progressed in 15mg increments using a 3+3 design. Part 2 is an expansion cohort recruiting 20 patients randomized to administration in fed or fasted states at the MTD. Results: Part 1 is complete and reported here. Nine patients were recruited and an MTD of 60mg was determined. DLTs were hyperglycemia and oral mucositis. AEs were generally reversible and consistent with the PI3K inhibitor class with the most common events were rash, oral mucositis, and fatigue. PK at the MTD was broadly consistent with the data published for the phase 1 study. For eight response-evaluable patients in Part I the median progression-free survival (PFS) was 8.4 months, and 25% of patients remained progression free after 15 months of follow-up. Part 2 is ongoing. Conclusions: A higher MTD of 60mg was identified in newly diagnosed GBM with unmethylated MGMT promotor status than the 45mg MTD previously identified in recurrent high-grade glioma. An encouraging PFS signal is described in this poor-prognosis, unmethylated MGMT patient population. Clinical trial information: NCT03522298 .

A phase I, open-label study of the safety and pharmacokinetics (PK) of pazopanib (P) and lapatinib (L) administered concurrently

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3088-3088 ◽  
Author(s):  
M. Dejonge ◽  
S. Savage ◽  
J. Verweij ◽  
T. S. Collins ◽  
F. Eskens ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Aggressive Fibromatosis ◽  
Clinical Activity ◽  
Concurrent Administration ◽  
Open Label ◽  
Once Daily ◽  
Open Label Study ◽  
Disease Stabilization ◽  
Hair Depigmentation

3088 Background: P is a potent tyrosine kinase inhibitor of VEGF-R1, -R2, and R3, PDGF-α/β, and c-Kit. L is a potent inhibitor of ErbB1 and ErbB2 tyrosine kinases. Several lines of evidence support combined inhibition of VEGFR and Erb in the treatment of malignancies. Methods: Patients (pts) with solid tumors received P and L daily. Safety, limited PK, biomarkers, and clinical activity were evaluated. Dose escalation occurred in cohorts of 3–6 pts based on DLT. Results: Thirty-three pts received L/P doses of 750/250 (n=4), 750/500 (n=6), 1000/250 (n=3), 1000/400 (n=2), 1000/500 (n=4), 1250/250 (n=6), 1250/400 (n=5) and 1500/200 (n=3) mg once daily (qd). Preliminary mean plasma P concentrations 24 h after administration (C24) on Day 22 were ∼19 μg/mL and 23 μg/mL after administration of 250 mg and 500 mg, respectively. These values are similar to mean C24 values observed after administration of 800 mg P alone (23.1 μg/mL). Plasma L concentrations at 750 - 1500 mg qd were similar to those observed after monotherapy. The most frequent AE’s were diarrhea (Grade (G)1 n=10, G2 n=2, G3 n=3), fatigue (G1: n=7, G2 n=5, G4 n=1), nausea (G1 n=9, G2 n=2), anorexia (G1 n=8, G2 n=3), vomiting (G1 n=9), hair depigmentation (n=7), rash (G1 n=6, G2 n=1) and abdominal cramps (G1 n=3, G2 n=2, G3 n=1). Prolonged disease stabilization of > 16 wks (median 21.5 wks) occurred in 10 pts (RCC n=3, CRC n=3, GIST n=1, mesothelioma n=1, adenocarcinoma GE junction n=1, aggressive fibromatosis n=1). 3 pts (renal cancer n=2, and giant cell tumor of the bone n=1) demonstrated tumor shrinkage of < 30% (i.e. SD by RECIST). Conclusions: Concurrent administration of pazopanib and lapatinib was generally well tolerated. Coadministration of lapatinib may alter the PK of pazopanib. [Table: see text]

A first-in-human dose phase 1 study of LY3009120 in advanced cancer patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2507-2507 ◽  
Author(s):  
David S. Hong ◽  
Antoine Hollebecque ◽  
Michael S. Gordon ◽  
Keith T. Flaherty ◽  
Geoffrey Shapiro ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Dose Escalation ◽  
Phase 1 ◽  
Performance Status ◽  
Tumor Growth Inhibition ◽  
Phase 2 ◽  
Advanced Cancer Patients ◽  
Phase 1 Study ◽  
Kras Mutations ◽  
Human Dose

2507 Background: LY3009120, a pan-Raf and dimer inhibitor, demonstrates inhibition of phospho-Mek/Erk and tumor growth inhibition in several non-clinical cancer models with BRAF, NRAS, or KRAS mutations. This is the first-in-human phase 1 study of LY3009120 in patients (pts) with advanced cancer. Methods: The safety and tolerability of LY3009120 was evaluated in pts with cancer aged 18 years or older who had an ECOG performance status ≤1, at least 1 unidimensionally measurable lesion (RECIST 1.1), and adequate organ function (NCT02014116; I6X-MC-JBDA; Eli Lilly & Co.). The study sought to determine a recommended phase 2 dose using the toxicity band method and the safety, pharmacokinetic, and preliminary efficacy of LY3009120. Pharmacodynamic (PD) biomarkers, including pERK, p27 and Ki67, were evaluated in tumor tissue. The dose escalation phase evaluated dosages from 50 mg to 500 mg by mouth twice daily in pts with advanced cancers. Results: 34 pts (3 at 50 mg, 4 at 100 mg, 3 at 200 mg, 15 at 300 mg, 7 at 400 mg, and 2 at 500 mg) in dose escalation and 1 pt in dose expansion (1 at 300 mg) received at least one dose of LY3009120 by January 2, 2016 (median age = 47.4 yrs, range: 26-82 ). Most pts had a gene mutation (BRAF, n = 7; N/KRAS, n = 18); the most common cancer types included colon (n = 9), non–small cell lung cancer (n = 8), and pancreatic (n = 5). There were 6 dose-limiting toxicities in the dose escalation phase: 2 pts at 300 mg (G3 dermatitis acneiform [n = 1] and G2 blurred vision [n = 1]); 2 pts at 400 mg (G2 increased ALT with G3 hyperbilirubinemia [n = 1] and G3 increased ALT [n = 1]); 2 pts at 500 mg: (G3 arthralgia/myalgia [n = 1] and G3 stomatitis/pain [n = 1]). Based on these data, the maximum tolerated dose for LY3009120 was determined to be 300 mg twice daily. Treatment-emergent adverse events related to LY3009120 occurring in ≥10% of pts included fatigue (34%), nausea (31%), decreased appetite (20%), and dermatitis acneiform (20%) (Grade 1,2). A dose proportional increase in exposure was observed, but not at the 400 mg dose. The best response was stable disease in 5 pts. PD effect by rtPCR was not observed in tested paired tumor samples. Conclusions: LY3009120 is well tolerated at doses of 300 mg twice daily. Updated data from dose expansion will be presented in the meeting. Clinical trial information: NCT02014116.

A phase I study of SRA737 (formerly known as CCT245737) administered orally in patients with advanced cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2607-TPS2607
Author(s):  
Maxime Chenard-Poirier ◽  
Alvaro Henrique Ingles Garces ◽  
Robert Hugh Jones ◽  
Amy Quinton ◽  
Elizabeth R. Plummer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Advanced Cancer ◽  
Dose Escalation ◽  
Phase 1 ◽  
Performance Status ◽  
Single Agent ◽  
Cell Cycle Checkpoint ◽  
Phase 2 ◽  
Regulatory Review

TPS2607 Background: SRA737 is a highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key cell cycle checkpoint and central regulator of the DNA Damage Response (DDR) network. In cancer cells, replication stress induced by genomic alterations in oncogenes (eg, MYC and RAS) combined with loss of function in tumor suppressors (eg, TP53 and ATM) results in persistent DNA damage and genomic instability. Targeted inhibition of components of the DDR network such as Chk1 by SRA737 may be synthetically lethal to cancer cells and have utility as a monotherapy in a range of tumor indications. SRA737 is currently being investigated in two Phase 1 trials in patients with advanced cancer. We now describe the Phase 1 multicenter, dose-escalation, monotherapy study of SRA737 (NCT02797964). Methods: Up to 40 patients with advanced cancer will receive oral SRA737 administered daily on a 28-day schedule. For dose-escalation, an accelerated titration design with 100% dose escalation and single patient cohorts is allowed until Grade 2 related toxicity is observed, followed by a rolling-6 design. Dose expansion will include 6 patients with any solid tumor treated at the recommended Phase 2 dose (RP2D). Eligibility criteria include WHO performance status of 0-1 and ≤ 3 prior lines of cytotoxic chemotherapy for metastatic disease. Primary objectives are to assess the safety profile of monotherapy SRA737 and to establish a RP2D. The PK profile and PD biomarkers will be investigated. The study was opened to enrollment in mid-2016. An amendment, which includes the addition of indication specific expansion cohorts of subjects with genetically-defined tumors known to have Chk1-sensitizing aberrations such as gene mutations and amplifications/deletions, has been submitted and is pending regulatory review while enrollment continues. At the Annual Meeting, the amended design will be described. The dose and schedule identified in this trial will inform the design and conduct of Phase 2 studies of SRA737 as a single agent and in combination with other targeted or immunomodulatory agents. Clinical trial information: NCT02797964.

A phase Ib trial of cabozantinib in combination with durvalumab (MEDI4736) in previously treated patients with advanced gastroesophageal cancer and other gastrointestinal (GI) malignancies (CAMILLA).

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. TPS56-TPS56 ◽  
Author(s):  
Anwaar Saeed ◽  
Devin Koestler ◽  
Stephen K. Williamson ◽  
Joaquina Celebre Baranda ◽  
Weijing Sun ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Dose Escalation ◽  
Tyrosine Kinases ◽  
Checkpoint Inhibitors ◽  
Standard Dose ◽  
Phase 1 ◽  
Single Agent ◽  
Primary Objective ◽  
Current Standard ◽  
Open Label

TPS56 Background: GI malignancies including Gastric (GC), esophageal (EAC), colon (CRC), and hepatocellular carcinoma (HCC) remain a significant health problem in the US & globally. The current standard upfront therapy has < 12 month median survival. Hypoxia mimetic agents such as VEGFR targeted therapy down regulate the angiogenesis pathway and sensitize tumors to chemotherapy. Cabozantinib targets multiple tyrosine kinases, including VEGFR, MET, and AXL, and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with PD-1 or PD-L1 inhibitors. We believe that modulating the tumor microenvironment with small molecule inhibitors like cabozantinib will have synergistic effect when combined with checkpoint based immunotherapy like durvaluamb in patients with chemo refractory GC, EAC, CRC and HCC. Methods: The study is funded by research grants from both Exelixis and AstraZeneca. A phase 1 dose escalation is followed by an open-label single arm expansion. Dose escalation will be conducted using a 3+3 design. Starting dose for cabozantinib is 20mg daily. Single agent durvalumab MTD has been used, given that a regimen with full dose durvalumab may be better accepted as a backbone for comparison in future studies. MTD of cabozantinib in combination with standard dose durvalumab will be defined as the highest safely tolerated dose where 0/6 or 1/6 patients experience a DLT and ≥ 2 patients have experienced a DLT at the next higher dose level. Primary objective is to determine the Recommended Phase 2 Dose (RP2D). Secondary objectives include safety, ORR, PFS and OS. Eligible patients received > 1 line of therapy, no prior checkpoint inhibitors, have measurable disease, & ECOG PS 0-1. Phase 1 dose escalation will enroll 9-18 patients and the expansion phase will enroll 12-21 patients. Correlative studies include assessment of tumor microenvironment, angiogenesis & immune molecular markers. The dose escalation phase is currently enrolling. Clinical trial information: NCT03539822.

A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654 administered daily for 28 days to patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3586-3586
Author(s):  
Ignacio Garrido-Laguna ◽  
Patrick Michael Dillon ◽  
Stephen Patrick Anthony ◽  
Margit Janat-Amsbury ◽  
Nissa Ashenbramer ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Peripheral Blood Mononuclear

3586 Background: TP-3654 is an oral, second generation, potent PIM-1 kinase inhibitor with activity against PIM 2, 3 and favorable selectivity against other kinases. These cytoplasmic serine/threonine kinases are highly expressed in many cancers and their oncogenic potential has been largely attributed to supressing apoptosis downstream of stimuli including inflammatory cytokines and other immune effectors. TP-3654 has efficacy in various hematologic and solid tumor models inducing stromal Pim-1 also has been shown to mediate various aspects of the tumor microenvironment. Thus, Pim kinases are attractive targets for the treatment of many human malignanices. Methods: A first in human, multicenter, phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-3654 in patients with advanced solid tumors. Results: Ten patients were enrolled between 30Apr and 31Dec2019 receiving 480, 720, and 1080 mg respectively. Grade 3 AEs were scrotum wound infection, altered mental status, anemia, fall, and lower extremity edema, none were related to study drug and all were manageable with supportive care. There were no Grade 4 or 5 AEs and no DLTs. Median duration of SD was 5.5 months (6/10) and with prolonged SD > 16wks (4/10). One CRC patient with 4 lines of prior therapy had a 22% reduction in tumor volume (SD > 5+ mos). TP-3654 plasma PK values (Cmax, AUC) continuously increased through all 3 cohorts. Average Cmax (ng/mL) and AUC0-24 (ng*hours/mL) were 195, 1965 (480mg); 357, 3310 (720mg); 735, 6922 (1080mg), respectively. PK values increased linearly with higher doses without reaching saturation. Peripheral Blood Mononuclear Cells were isolated from subjects prior and up to 24hours after treatment. Western Blot from protein lysates revealed a decrease in phosphorylation of BAD and p70s6K proteins, both regulated by PIM-1 kinase. Conclusions: These findings suggest that TP-3654 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, and resistant solid tumors warranting further clinical development in selected indications.

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