Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in patients with advanced pancreatobiliary cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3051-3051
Author(s):  
Nebojsa Skorupan ◽  
Mehwish Iqra Ahmad ◽  
Guillaume Joe Pegna ◽  
Cody J. Peer ◽  
Jane B. Trepel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Primary Objective ◽  
Pseudomonas Exotoxin A ◽  
Recombinant Immunotoxin ◽  
Level 1 ◽  
Expansion Cohort ◽  
Almost All

3051 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload to tumors. Previous clinical trials demonstrated that almost all patients formed anti-drug-antibodies (ADAs) to LMB-100 that made administration beyond cycle 2 ineffective. Tofacitinib is an oral JAK inhibitor that prevented formation of ADAs against a closely related immunotoxin in pre-clinical studies. The primary objective of the dose escalation cohort was assessment of safety and tolerability of LMB-100 given with tofacitinib to patients with mesothelin-expressing solid tumors. The primary objective of the expansion cohort was to determine whether co-administration of tofacitinib delays formation of neutralizing LMB-100 ADAs. Methods: Patients (n = 13) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 mcg/kg) and co-treated with oral tofacitinib for the first 10 days of the cycle (10 mg BID). Results: Dose level 1 of LMB-100 was started at 100 mcg/kg one dose level below the single agent MTD. Dose escalation to 140 mcg/kg (dose level 2) resulted in DLTs in 2 of the 3 patients treated: grade 3 cardiac toxicity and grade 4 hyponatremia, both attributed to capillary leak syndrome. Ultimately, 7 patients were treated at dose level 1 without DLTs and 100 mcg/kg was chosen as the LMB-100 dose for the expansion cohort. The last of 6 patients treated in the expansion cohort developed grade 4 pericardial effusion leading to early closure of the study for toxicity. No objective responses were seen. Of the 8 patients who received two cycles of treatment at MTD, 4 met prespecified criteria for ADA prevention, and 2 patients who went on to receive cycle 3 had detectable LMB-100 plasma drug levels after administration. Conclusions: LMB-100 was unable to be co-administered safely with tofacitinib. ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence. Clinical trial information: NCT04034238.

A phase I trial of the oral hedgehog inhibitor taladegib (LY2940680) in combination with weekly paclitaxel in patients with advanced, solid tumours.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2594-2594
Author(s):  
Rosalind Margaret Glasspool ◽  
Sarah Patricia Blagden ◽  
Michelle Lockley ◽  
James Paul ◽  
Carol Hopkins ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Primary Objective ◽  
Solid Tumours ◽  
Muscle Cramp ◽  
Weekly Paclitaxel ◽  
Level 1 ◽  
Level 2

2594 Background: Aberrant Hedgehog (Hh) signaling is implicated in carcinogenesis and is associated with poor prognosis in multiple tumours types. Hh inhibitors increase sensitivity to paclitaxel in taxane-resistant cell lines. Taladegib is an orally bioavailable, potent inhibitor of Smoothened, a key Hh pathway component, with activity in basal cell carcinoma. The single agent recommended dose is 400mg od. We present the dose escalation phase of a phase I study of weekly paclitaxel with oral taladegib. Methods: Primary objective: determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of taladegib on a continuous oral daily dosing regimen in combination with paclitaxel (80mg/m2, iv, day 1, 8 and 15 q 28) in patients with advanced solid cancers. Secondary objectives: assess the safety and tolerability, determine the recommended phase II dose (RP2D), and evaluate the pharmacokinetics of taladegib and paclitaxel. Exploratory objective: assess preliminary efficacy. A standard 3 + 3 dose escalation design was used. All patients received up to 6 cycles of paclitaxel. In addition, successive cohorts received continuous oral taladegib continued until progression or unacceptable toxicity as follows: dose level 1: 100mg od; 2: 200mg od; 3: 400mg od. Results: No DLTs were seen at dose level 1 or in the first 3 patients at dose level 2. 3 DLTs of grade 2 neuropathy were seen at dose level 3 (400mg taladegib); therefore, dose level 2 was expanded to 6 patients. No DLT was seen in the fourth patient and 2 additional patients have started treatment. After the DLT period 2 patients developed G2 and 4 developed G1 neuropathy. Other non DLT, drug-related G3 toxicities: uncomplicated neutropenia x2, muscle cramp x1 and fatigue x1. To date, 3 patients have had partial responses. Conclusions: The combination of daily oral taladegib and weekly paclitaxel is feasible. DLT of G2 neuropathy was seen at 400mg. Promising activity has been seen in solid tumours. A dose expansion cohort is due to commence in high grade ovarian carcinoma. ISRCTN No:ISRCTN15903698 Eudract Ref:2014-004695-37 Funded by Cancer Research UK C8361/A18775 and Ignyta. Sponsored by NHS Greater Glasgow and Clyde. Clinical trial information: ISRCTN15903698.

CTNI-36. SAFETY OF ONC201 ADMINISTERED TWO CONSECUTIVE DAYS PER WEEK IN PEDIATRIC H3 K27M-MUTANT GLIOMA PATIENTS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi67-vi67
Author(s):  
Sharon Gardner ◽  
Carl Koschmann ◽  
Rohinton Tarapore ◽  
Jeffrey Allen ◽  
Wafik Zaky ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Safety Data ◽  
Study Drug ◽  
Abducens Nerve ◽  
Biologically Active ◽  
Phase Ii Trials ◽  
Level 1 ◽  
Expansion Cohort

Abstract ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. The recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated in adult and pediatric populations. Radiographic regressions with single agent ONC201 have been reported in recurrent H3 K27M-mutant glioma patients. In another study, twice/week dosing was explored in adult patients and deemed to be safe (no DLTs observed). This warranted exploration of twice/week dosing in pediatric patients and will be discussed in this presentation. This multi-arm, dose-escalation and dose-expansion trial (ONC014; NCT03416530) determined the pediatric RP2D of ONC201 administered once per week and twice per week on two consecutive days. ONC201 was orally administered and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with two 125mg capsules less than the adult RP2D equivalent. Twelve children (8 females; 4 males) with H3 K27M-mutant gliomas (pons: 8; thalamus: 2; spinal cord: 2) aged 4-19 years have been treated post-radiation: 3 at dose level -1; 3 at dose level 1; 6 as part of the dose expansion cohort on dose level 2. Median KPS was 90 (range 70-100). One treatment cycle was 21 days (6 doses), which also defined the DLT window. Patients were on-treatment for a median length of 4 cycles (range: 2-11). Twice weekly dosing of ONC201 was tolerated well, as observed with weekly dosing, with no instance of DLT. A total of 4 SAEs were reported, none of which were related to the study drug. The most common AEs (regardless of relatedness) included headache, facial nerve disorder, abducens nerve disorder, nausea, fatigue and ataxia. Additional safety data, PK, and clinical outcomes from this arm will be reported.

Phase 1 and phase 2a, first-in-human (FIH) study, of DRP-104, a broad glutamine antagonist, in adult patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3149-TPS3149
Author(s):  
Melissa Lynne Johnson ◽  
Deborah Blythe Doroshow ◽  
Tanguy Y. Seiwert ◽  
Michael K. Gibson ◽  
Vamsidhar Velcheti ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Primary Objective ◽  
Adult Patients ◽  
Glutamine Metabolism ◽  
Advanced Solid Tumors

TPS3149 Background: Dependence of cancer cells on glutamine has made glutaminolysis an attractive therapeutic target in cancer. Prior clinical trials evaluating glutamine analogues for the treatment of cancer were abandoned due to lack of efficacy and/or tolerability. DON (6-Diazo-5-oxo-L-norleucine) is an irreversible inhibitor of several enzymes that utilize glutamine as a metabolic substrate. In addition to direct anti-tumor efficacy, inhibition of glutamine metabolism in the tumor microenvironment has been shown to improve T-cell activation and tumor infiltration, increasing anti-tumor immune responses. As such, combining DON with an immune checkpoint inhibitor (ICI), has strong preclinical rationale. The investigational product DRP-104 (sirpiglenastat) is an inactive prodrug of DON designed to limit systemic DON exposure while targeting glutamine dependence in tumor cells. Methods: A phase 1/2a, FIH, multi-center, non-randomized, multi-cohort, open-label study of DRP-104 is currently open to accrual for patients with advanced solid tumors. This study will be conducted in 4 parts: A) Dose Escalation of IV and subQ DRP-104 (Run-In phase followed by modified Continual Reassessment Method) to define MTD/RP2D. Primary objective of dose escalation is to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of DRP-104 as a single agent; B) Dose Expansion of IV and subQ DRP-104 for safety assessment while primary objective is to select and recommend phase 2 DRP-104 route of administration; C) Phase 2a at recommended MTD/RP2D of selected route of DRP-104 in 2 patient cohorts: patients with locally advanced/metastatic NSCLC with KEAP1, NFE2L2 and/or STK11 mutation and patients with unresectable or metastatic SCCHN, in order to assess the safety, tolerability and preliminary antitumor activity of DRP-104 as a single agent; D) Phase 2a at recommended MTD/RP2D of selected route of DRP-104 in combination with atezolizumab in adult patients with advanced solid tumors previously treated with an ICI, in order to assess the safety, tolerability and preliminary antitumor activity of DRP-104 in combination with atezolizumab; DRP-104 IV is infused TIW over 1 hour infusion for 2 consecutive weeks followed by 1 week off. DRP-104 subQ is administered BIW weekly. Study is currently open with 6 IV patients (Run-In Phase completed and at Dose Level 4) and 3 subQ patients at Dose Level 1 at time of submission. Clinical trial information: NCT04471415.

Phase I dose-escalation, open-label study of HSP990 administered orally in adult patients with advanced solid malignancies.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2561-2561
Author(s):  
Leticia De Mattos-Arruda ◽  
Lillian L. Siu ◽  
Javier Cortes ◽  
Yann Berge ◽  
Albiruni R A Razak ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Standard Therapy ◽  
Metabolic Response ◽  
Single Agent ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Oncogenic Signaling ◽  
Open Label ◽  
Solid Malignancies

2561^ Background: NVP-HSP990 is a synthetic small molecule that potently and selectively inhibits heat-shock protein 90. HSP990 leads to degradation of client proteins, offering potential simultaneous blockade of multiple oncogenic signaling pathways. The primary objective of this Phase l first-in-man study (NCT00879905) was to determine the single-agent MTD of HSP990 administered once (qw) or twice (biw) weekly to patients (pts) with advanced solid malignancies (preselected CYP2C9 genotypes only). Secondary objectives included safety, efficacy, PK, and biomarkers. Methods: HSP990 was administered orally qw or biw in 28-day cycles. Dose escalation was guided by a Bayesian logistic regression model. The MTD was determined by assessing DLTs in Cycle 1. Eligible pts included those with histologically confirmed advanced solid tumors that had progressed on standard therapy or for whom no standard therapy exists. Results: 64 pts (median age 57 yr: 44% male; 37.5% Stage IV; WHO PS 0/1) received HSP990. 53 pts received HSP990 qw at 2.5, 5, 10, 20, 30, 50 or 60 mg; and 11 pts received HSP990 biw at 25 mg. Median duration of exposure was 8 wks; 12 pts remained on treatment for >16 wks. DLTs occurred in 7 pts: 4/22 at 50 mg qw (including G3 diarrhea, G3 QTc prolongation, G4 ALT/AST elevations); 2/5 at 60 mg qw (including G3 tremors); and 1/11 at 25 mg biw (including G2 ataxia, G2 confusion, G2 visual hallucination). The 50-mg qw dose was declared as the MTD. Further dose escalation was not possible due to neurologic toxicity. Most common reported CTCAE G3/4 AEs were diarrhea (12.5%), increased ALT/AST (11% each), anemia, or cholestasis (6% each). HSP990 had Tmax of 3 h and T½ of ~20 h. Large inter-patient variability in PK exposures was observed. For qw dosing, approximate dose-dependent HSP70 induction was observed from 5−30 mg qw, which plateaued after 20 mg qw. There were no objective responses; however, 25 pts (39%) had SD. (RECIST v1.0). No pt showed a complete metabolic response (MR; by FDG-PET) and 11 pts (17%) showed a partial MR. All pts discontinued treatment, primarily due to disease progression (84%). Conclusions: The single-agent MTD of HSP990 in pts with advanced solid tumors was 50 mg qw. SD was observed in 39% of pts. Clinical trial information: NCT00879905.

Pooled analysis of phase I dose-escalation and dose cohort expansion studies of IMP4297, a novel PARP inhibitor, in Chinese and Australian patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
Junning Cao ◽  
Pin Zhang ◽  
Paul L. de Souza ◽  
Bo Gao ◽  
Mark Voskoboynik ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Response To Treatment ◽  
Clinical Activity ◽  
Dose Cohort ◽  
Phase Ii Studies ◽  
Grade 3

3059 Background: Poly (ADP-ribose) polymerase (PARP) enzymes play critical roles in DNA damage detection and repair. IMP4297 is a novel, potent PARP1/2 inhibitor (IC50 6.27nM/1.57nM) and has demonstrated to be 20-fold more potent than Olaparib in anticancer animal models. Two phase I studies were performed to evaluate and characterize the tolerability and safety, pharmacokinetics, and antitumor activity of single agent IMP4297 in Chinese and Australian patients with advanced ovarian, breast, prostate and other solid tumors. Methods: Dose escalation used a 3+3 design with a modified Fibonacci escalation. Dose cohort expansion was planned after efficacy was observed at the lowest dose level. Patients received IMP4297 monotherapy orally once a day until disease progression or unacceptable toxicity. Results: As of Jan 12, 2019, 56 patients, including 23 BRCA mutation carriers (BRCA+), had been enrolled at 2-100 mg dose level. No DLT was observed. In these two studies, the most frequent treatment-related adverse events (TRAEs) were leukopenia (20%), followed by anemia (18%), nausea (18%) and thrombocytopenia (14%). The majority of TRAEs were grade 1 or 2. Grade 3 TRAEs occurred in five patients (anemia, n=2; vomiting, n=1; thrombocytopenia, n=1; elevated AST, n=1). Only one patient had a dose reduction due to grade 3 thrombocytopenia. No serious TRAEs were observed. In 15 BRCA+ patients who had measurable lesions, the ORR was 33% and the DCR was 80%. There were 4 BRCA+, platinum-sensitive ovarian cancer patients with an ORR of 75% and a DCR of 100%. One patient with somatic BRCA mutated urothelial carcinoma showed a 76% decrease in tumor size. Conclusions: IMP4297 has been well-tolerated with significant anti-tumor activity. The 100 mg daily dose was selected as the RP2D based on safety, pharmacokinetics and clinical activity, and will be further characterized in dose expansion and phase II studies. Tumor response to treatment (RECIST 1.1) in patients with measurable lesions. Clinical trial information: NCT03508011 and NCT03507543. [Table: see text]

Phase I study of mesothelin-targeted immunotoxin LMB-100 given as a long infusion with or without nab-paclitaxel.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3553-3553
Author(s):  
Guillaume Joe Pegna ◽  
Mehwish Iqra Ahmad ◽  
Yunkai Yu ◽  
Akira Yuno ◽  
Min-Jung Lee ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Pancreatic Adenocarcinoma ◽  
Peak Plasma ◽  
High Titer ◽  
Phase 1 ◽  
Single Agent ◽  
Pseudomonas Exotoxin A ◽  
Short Infusion ◽  
Recombinant Immunotoxin ◽  
Dose Levels

3553 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload. Previous Phase 1 clinical testing of a 30-minute LMB-100 “short” infusion format identified a serum half-life of ~1 hour. Pre-clinical data suggested that extending infusion time could improve anti-tumor efficacy by increasing tumor cell duration of exposure to LMB-100. The primary objective of this study was to determine the safety and tolerability of administering LMB-100 in a long infusion format over 24-48 hours alone or with nab-paclitaxel chemotherapy in patients with mesothelin-expressing solid tumors. Methods: Patients (n = 15) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; mesothelioma, colon, and ampullary cancers) treated on 3 dose levels received long infusion of LMB-100 (65 or 100 mcg/kg/day) for 24 hour on Days 1 and 4 (n = 6) or 48 hour on Day 1 (n = 9) with or without a loading dose (40 mcg/kg over 30 minutes) for up to 2 cycles. In the second arm, patients (n = 5) with pancreatic adenocarcinoma were treated with LMB-100 over 24 hours on Day 1 concurrently with nab-paclitaxel (125 mg/m2) for up to 3 cycles. Results: DLT of proteinuria (grade 3) in one patient and acute kidney injury (grade 1) in one patient were observed amongst patients receiving 100 mcg/kg/day over 48 hours and 24 hours, respectively. No objective responses were seen but all patients receiving nab-paclitaxel had > 50% decrease in CA 19-9. Patients at all single agent dose levels (8 of 10 evaluable) developed high titer anti-drug antibodies (ADAs) against LMB-100. Those with ADAs (8 of 8) had undetectable cycle 2 peak plasma LMB-100 concentration. Development of high titer ADAs occurred more frequently with long infusion than seen previously with “short” infusion LMB-100. Most long infusion patients (19 of 20) developed increased serum IL-6 within 24 hours of LMB-100 infusion. However, the systemic inflammatory response to LMB-100 (as measured by increased serum CRP) which occurs in most “short” infusion patients was not observed. Conclusions: Long infusion format LMB-100 is generally well tolerated but immunogenicity limits treatment to 1 effective cycle. No anti-tumor efficacy of the single agent was observed. Clinical trial information: NCT02810418 .

Phase Ib clinical study of CBP501, cisplatin, and nivolumab administered every three weeks in patients with advanced refractory tumors: Efficacy in dose-escalation and expansion cohorts.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3059-3059
Author(s):  
Marc Ryan Matrana ◽  
Frank Tsai ◽  
James M. Cleary ◽  
Suma Satti ◽  
Erkut Borazanci ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Dose Escalation ◽  
Epithelial Mesenchymal Transition ◽  
Single Agent ◽  
Locally Advanced ◽  
Mesenchymal Transition ◽  
Phase Ib ◽  
Expansion Cohort

3059 Background: CBP501 is a 12-amino acid G2 checkpoint abrogator and calmodulin-modulating peptide that increases platinum influx into tumor cells and induces tumor immunogenic cell death. CBP501 also suppresses platinum-induced release of cytokines by macrophages, lowers cancer stem cell populations, and reduces migration, invasion, and epithelial-mesenchymal transition of tumor cells. We report safety and efficacy outcomes from dose-escalation and expansion cohorts of a Phase Ib study of CBP501 combined with cisplatin and nivolumab (NCT03113188). Methods: An open-label Phase I trial was conducted using a 3+3 design: CBP501 and cisplatin were dosed simultaneously by 1h infusion Q3W at 4 different combined dose levels (CBP501: 16 or 25 mg/m2; cisplatin: 60 or 75 mg/m2) in the dose-escalation cohort. Nivolumab (240 mg) was dosed on the same day as a 1h infusion following CBP501/cisplatin. CBP501 and cisplatin were fixed at 25 and 60 mg/m2, respectively, in the expansion cohort. Eligible patients had pathologically confirmed, locally advanced or metastatic solid tumors, age ≥18 years, ECOG PS 0-1, life expectancy > 3 months. The dose-expansion cohort had pretreated metastatic exocrine pancreatic cancer or microsatellite stable colorectal cancer (CRC). Scans were performed every 6 weeks while on study, then every 3 months. Results: The most common related adverse events (AEs) were infusion-related reaction (rash, itching, hives; n = 32/37 [Gr 1, n = 4; Gr 2, n = 28]; 86%) and anemia (n = 19/37 [Gr 1/2, n = 10; Gr 3, n = 9]; 51%). There were no additional safety signals other than those known for each agent. At January 9, 2020 (interim analysis), efficacy was evaluable in 17/19 patients in the dose-escalation cohort. Unconfirmed partial response was seen in 18% (3/17; 1 pancreatic, 1 colorectal, 1 cholangiocarcinoma), with > 3 months stable disease (SD) in 41% (7/17), disease control in 41% (7/17), and > 8 months overall survival (OS) in 53% (9/17). In the expansion cohort, efficacy was evaluable in 8/13 patients with pancreatic cancer: > 4 months SD was 50% (4/8), median progression-free survival 4.2 months, and median OS 5.9 months (6/8 ≥3rd line). The CRC cohort median OS for all CRC patients (n = 10) including the dose-escalation cohort (n = 5) was 17.5 months (10/10 ≥3rd line). Conclusions: The triple-drug combination is reasonably tolerable with preliminary signs of efficacy in refractory solid tumors, including those in which cisplatin and nivolumab have limited single-agent activity. Clinical trial information: NCT03113188 .

Preliminary efficacy from an ongoing phase 1 dose escalation study of seclidemstat (SP-2577) in patients (pts) with advanced solid tumors (AST).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3073-3073
Author(s):  
Sant P. Chawla ◽  
Victoria S. Chua-Alcala ◽  
Jasgit C. Sachdev ◽  
David S. Wages ◽  
David D. Stenehjem ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Phase 1 Trial ◽  
Ongoing Phase

3073 Background: Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that is aberrantly expressed in many solid tumors. High levels of LSD1 expression are often correlated with poor patient prognosis due to LSD1’s role in cancer cell proliferation, metastasis, and chemoresistance. Seclidemstat is a novel, selective, reversible and oral LSD1 inhibitor capable of inhibiting both LSD1’s catalytic and scaffolding functions. We report preliminary efficacy in AST from an ongoing phase 1 trial. Methods: SALA-003-AC19 (NCT03895684) is a phase 1 trial of single agent SP-2577 in pts with AST. All pts had progressive disease (PD) at time of study entry. Pts received oral SP-2577 twice a day under fasting condition, in 28-day cycles (C). The primary objective is safety and tolerability. Secondary objectives are to determine maximum-tolerated dose, preliminary efficacy, pharmacokinetics, and pharmacodynamics. Results: As of December 30, 2020, 19 pts with AST (10 sarcoma, 2 prostate, 2 ovarian, 2 pancreatic, 1 renal, 1 cervical, 1 breast) were enrolled. Pts received escalating doses of SP-2577 from 150 to 600 mg BID and the dose escalation is ongoing. The median age was 63 years (range, 21–79). 42% were male, and pts had received a median of 4 (range, 1–8) prior systemic therapies. The most common (>5%) grade 3 treatment-related adverse events were GI related including diarrhea (5.3%) and abdominal pain (5.3%). No grade 4 events were reported and there were no treatment-related deaths. Safety data will be presented after completion of phase 1. Three pts had at least one dose reduction. Among the 13 pts who were evaluable for response at end of C2, 7 pts (54%) had best response of stable disease (SD) with median time to progression (TTP) of 4.3 months (range, 2.1–11.5). Four of the 7 pts had genetic abnormalities that may demonstrate increased sensitization to SP-2577 according to preclinical studies. Characteristics of 7 pts with SD at C2 and beyond are shown in the table. Conclusions: Seclidemstat has shown activity among advanced sarcoma pts with a manageable safety profile. The dose escalation is ongoing and preliminary clinical data supports further exploration in FET-translocated sarcoma as single agent and in combination therapy. Clinical trial information: NCT03895684. [Table: see text]

Phase I safety and tolerability of once daily oral afatinib (A) in combination with gemcitabine (G) in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13009-e13009 ◽  
Author(s):  
Sylvie Zanetta ◽  
Jaafar Bennouna ◽  
Nicolas Isambert ◽  
Helene De-Montserrat ◽  
Patrick J. Squiban ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Primary Objective ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Once Daily ◽  
Initial Starting

e13009 Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability and pharmacokinetics of A in two parallel dose cohort expansion parts, in combination with either G (Part A) or docetaxel (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part A are presented here. Methods: Eligible patients (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once-daily, oral dosing of A in combination with G, given intravenously at Day 1 and at Day 8 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. The primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLTs) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 patients using a 3+3 design. Initial starting dose level was A 30 mg/day and G 1000mg /m², escalating up to A 50 mg/day and G 1250 mg/m², until the MTD was reached, and followed by a PK expansion cohort of 12 patients at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 19 patients have been treated on study with the following baseline characteristics: mean age (53.7 years), women (63.2%) and number of prior chemotherapies (≤2: 26%, >2: 74%). Twelve patients received 2–4 cycles of treatment and five patients received 4 or more cycles. AEs observed in most patients were diarrhea (89.5%) and rash (63.2%). In Cycle 1, DLTs were experienced by one patient out of six receiving A 30 mg and G 1250 mg/m². MTD was exceeded at a dose level of at least A 40 mg/day and G 1250 mg/m². An intermediate dose level of A 40 mg/day and G 1000 mg/m² is currently under evaluation. Conclusions: In patients with relapsed or refractory advanced solid tumors, the combination of A with G is well tolerated, with manageable AEs. Dose finding is ongoing and MTD, safety profile and preliminary evidence of activity are anticipated to be reported at time of presentation.

scholarly journals A Phase 1 Study of Tasquinimod in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-18
Author(s):  
Dan T. Vogl ◽  
Yulia Nefedova ◽  
E. Paul Wileyto ◽  
Harjeet Sembhi ◽  
Inna Strakovsky ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Optimal Schedule ◽  
Study Endpoint ◽  
Expansion Cohort

Background Multiple myeloma (MM) is a hematologic malignancy resulting from clonal proliferation of plasma cells in the bone marrow (BM). The BM tumor microenvironment confers therapeutic resistance through survival and growth signals to myeloma cells and suppression of anti-tumor immune responses. A population of myeloid-derived suppressor cells (MDSCs), abundantly producing the pro-inflammatory S100A9 protein, promotes myeloma progression. Tasquinimod (TASQ) is an investigational drug that targets MDSCs via the S100A9 protein. In pre-clinical models of MM, TASQ has significant anti-tumor effects as a single agent and in combination with bortezomib, a proteasome inhibitor (PI) and lenalidomide, an immunomodulator (IMiD) (Lin C, et al. 25th Annual Meeting of European Hematology Association June 11-21 2020: EP896). TASQ has previously been studied as a novel, once-daily oral anti-cancer agent, including in a phase-3 randomized trial in patients (pts) with metastatic prostate cancer that showed improvement in radiographic progression-free survival (Sternberg C, et al. JCO 2016; 34(22): 2636-43). The side effect profile of TASQ is well-characterized based on this previous experience. We therefore designed a phase 1 trial (NCT04405167) to establish the maximum tolerated dose (MTD) and optimal schedule for TASQ in MM and then investigate the MTD of TASQ in combination with a standard oral myeloma regimen of ixazomib, lenalidomide, and dexamethasone (IRd). For both single agent TASQ and the combination of TASQ with IRd, exploratory expansion cohorts will be enrolled to preliminarily characterize the antimyeloma activity of each regimen. Study Design Enrolled pts must have MM relapsed or refractory after at least one prior line of anti-MM therapy. Other key inclusion criteria include measurable disease and Eastern Cooperative Oncology Group performance status ≤2. Key exclusion criteria include failure to have fully recovered from clinically significant adverse effects of prior chemotherapy; active graft versus host disease; treatment with cytotoxic chemotherapy within 3 weeks prior to initiation of study treatment; treatment with PIs, IMiDs, or monoclonal antibodies within 2 wks, experimental therapy or plasmapheresis within 4 wks, or systemic corticosteroids or radiotherapy within 7 days; known central nervous system involvement by myeloma; or a diagnosis of smoldering MM or POEMS syndrome, active plasma cell leukemia, symptomatic primary amyloidosis, or myelodysplastic or myeloproliferative syndrome. Single agent TASQ and the combination of TASQ with IRd will be investigated in two parts. Part A will start with dose-escalation of single agent TASQ using a standard 3+3 design, with 3 to 6 pts evaluable for dose-limiting toxicity at each dose-level (see table). In the subsequent expansion cohort, additional pts will enroll at the MTD/optimal schedule, so that 12 pts total evaluable for response will have received the MTD/optimal schedule of single agent TASQ. Part B combines TASQ with standard-dose IRd: 28-day cycles of ixazomib 4 mg on days 1, 8, and 15, lenalidomide 25 mg on days 1-21, and dexamethasone 40 mg on days 1, 8, 15, and 22. The part B dose-escalation starts at the lower of either dose-level 1 or one dose-level below the single agent MTD. Additional pts with disease refractory to their most recent PI/IMiD combination will enroll into a part B expansion cohort, so that 12 pts total who are both evaluable for response and PI/IMiD refractory will have received the MTD/optimal schedule of TASQ in combination with IRd. Treatment will continue until unacceptable toxicity or myeloma progression. The primary study endpoint is the MTD of TASQ as single agent and in combination with IRd. Key secondary endpoints include toxicity (treatment-emergent grade 3/4 adverse events using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 5), preliminary antimyeloma activity (using the response criteria of the International Myeloma Working Group), changes in the BM microenvironment, and systemic TASQ exposure during therapy with single-agent TASQ and during therapy with TASQ in combination with IRd. These results will determine whether TASQ, alone or combined with standard anti-MM therapy, represents a promising novel treatment strategy in MM. Table 1 Disclosures Vogl: Active Biotech: Consultancy, Research Funding; Janssen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Oncopeptides: Consultancy; MorphoSys: Consultancy. Nefedova:Active Biotech: Consultancy, Research Funding. Bondesson:Active Biotech: Current Employment. Eriksson:Active Biotech: Current Employment. Tuvesson:Active Biotech: Current Employment. OffLabel Disclosure: Tasquinimod for multiple myeloma

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