BET inhibitor molibresib for the treatment of advanced solid tumors: Final results from an open-label phase I/II study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3618-3618 ◽  
Author(s):  
Sophie Cousin ◽  
Jean-Yves Blay ◽  
Irene Braña Garcia ◽  
Johann S. De Bono ◽  
Christophe Le Tourneau ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Treatment Discontinuation ◽  
Tolerability Profile ◽  
Repeat Dose ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Total Cohort ◽  
Tumor Types

3618 Background: Molibresib is an orally available, small molecule bromodomain and extra-terminal domain (BET) protein inhibitor under investigation for treatment of advanced solid tumors. Methods: This was an open-label, single- and repeat-dose, 2-part, Phase 1/2 study including patients (aged ≥16 years) with advanced solid tumors. Part 1: patients received different oral doses of molibresib (2–100mg QD; amorphous free-base formulation) to determine recommended Phase 2 dose. Part 2 (expansion cohort): patients with various tumor types received the bioequivalent besylate formulation (75mg) to explore clinical activity at recommended dose. Safety and efficacy (response rate [RR] based on RECIST 1.1 criteria, progression-free survival [PFS], and overall survival [OS]) were evaluated for the total cohort (patients from Part 1 and 2). Safety, pharmacokinetic, pharmacodynamic, and efficacy per tumor type were evaluated in Part 2. Results: Part 1 only data have previously been reported. Overall, 196 patients were included in the total cohort (1 patient in Part 1 was counted twice). In the all treated population, 195 patients (median age 58 years; 46% male) received ≥1 dose of molibresib (Part 1: n = 93; Part 2: n = 102). Adverse events (AEs) were experienced by 193/196 (98%) patients; 180/196 (92%) had a treatment-related AE (TRAE). AEs led to permanent treatment discontinuation in 38/196 (19%) patients. Of different tumor types in Part 2, NUT carcinoma (NC) had the lowest frequency of TRAEs (10/12 [83%]) and AEs leading to permanent treatment discontinuation (1/12 [8%]). In total cohort, 3/31 NC patients and 1/35 with castration-resistant prostate cancer (CRPC) achieved a confirmed partial response. A further 67/196 (34%) achieved stable disease (SD). In Part 2, RR in 12 NC patients was 8% (CI: 0.2–38.5); 50% had SD and median PFS was 4.8 months with median OS of 5.0 months. In CRPC patients, RR was 4% (CI: 0.1–21.9); 22% had SD; median PFS was 8.0 months with median OS of 9.1 months. Plasma concentrations for molibresib and active metabolites were similar between different tumor types. Gene expression analysis from pre- and post-dose biopsy samples collected from 10 mCRPC patients showed transcriptional downregulation of Myc target genes upon treatment with molibresib. Conclusions: Molibresib demonstrated a manageable safety and tolerability profile with single agent activity observed in selected patients with NC and CRPC. Clinical trial information: NCT01587703 .

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

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.

PLANETTE: A modular phase IIa multicenter open-label study evaluating the ATR inhibitor ceralasertib (AZD6738) in ATM mutant advanced solid tumors.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS189-TPS189
Author(s):  
Wassim Abida ◽  
Elkhan Sanay ◽  
Natalia Lukashchuk ◽  
Andrew Pierce ◽  
Wessel de Graaf ◽  
...  
Keyword(s):  
Dna Damage ◽  
Solid Tumors ◽  
Ataxia Telangiectasia ◽  
Synthetic Lethality ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Minor Response ◽  
Open Label Study ◽  
Label Study ◽  
Tumor Types

TPS189 Background: Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) are kinases that orchestrate cellular responses to DNA damage. ATM is primarily activated by DNA double strand breaks, and ATR is recruited to regions of single stranded DNA that arise due to collapsed or stalled replication forks. Although ATM and ATR are activated by distinct pathways, their downstream targets and effects partially overlap to activate cell cycle checkpoints and DNA damage repair. Ceralasertib is a potent, oral, selective inhibitor of ATR. Pre-clinical studies have consistently demonstrated synthetic lethality of ATR inhibitors, including ceralasertib, in ATM-deficient models across multiple tumor types (Kwok et al 2017, Min et al 2017, Lloyd et al 2020, Hustedt et al 2019). Early clinical evidence of efficacy is from a phase I study of ceralasertib in combination with olaparib in relapsed, refractory cancer (NCT02576444). Amongst 5 participants with a range of solid tumors harboring deleterious ATM mutations, there was 1 complete response, 3 stable diseases (1 with minor response 20-30%) and 1 patient with disease progression. Two participants had clinical benefit ongoing for more than 12 months (Eder et al 2019). ATM deficiency may be detected through genomic testing for loss-of-function alterations in the gene, or through immunohistochemical methods to detect loss of protein expression. Genomic alterations in ATM occur across multiple solid tumor types, including approximately 4% of advanced prostate cancers. Methods: PLANETTE (clinicaltrials.gov identifier (NCT 04564027) is a modular phase 2a multicenter open-label study investigating DNA-damage response agents in patients with advanced cancers that harbor molecular alterations. Module 1 will study the ATR inhibitor ceralasertib in tumors with deleterious or suspected deleterious mutations in ATM. Patients will be identified at cancer centers which routinely perform molecular profiling to detect ATM mutations. Central confirmation of ATM mutation by NGS and ATM IHC testing will be conducted retrospectively. Cohort A will enroll ~25 patients with advanced solid tumors (except NSCLC and prostate cancer), cohort B will include ~27 patients with metastatic CRPC who have previously progressed on a novel hormonal agent. The primary endpoints are investigator assessed ORR in Cohort A and composite response that includes radiographic, PSA, and CTC response per PCWG criteria in Cohort B. Secondary endpoints include duration of response, and progression free survival. Pharmacodynamic and other biomarkers will be explored. Enrolment is planned to start in November 2020. Clinical trial information: 04564027.

Phase I study of ispinesib in combination with carboplatin in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2027-2027 ◽  
Author(s):  
S. F. Jones ◽  
E. R. Plummer ◽  
H. A. Burris ◽  
A. R. Razak ◽  
A. A. Meluch ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Mitotic Spindle ◽  
Phase I Study ◽  
Single Agent ◽  
Tolerability Profile ◽  
Synergistic Activity ◽  
Platinum Compound ◽  
Advanced Solid Tumors ◽  
Carboplatin Auc

2027 Background: Kinesin spindle protein (KSP) is required for establishment of mitotic spindle bipolarity and cell cycle progression. Ispinesib (SB-715992), a KSP inhibitor, blocks assembly of a functional mitotic spindle leading to G2/M arrest. Carboplatin is a platinum compound that produces predominantly interstrand DNA cross-links. In vivo combination of a platinum-containing agent (cisplatin) and ispinesib resulted in synergistic activity and an increase in maximum tolerated dose (MTD) of ispinesib. In a phase I study of single agent ispinesib on a once every 21-day schedule, the MTD was 18 mg/m2 with prolonged gr 4 neutropenia and febrile neutropenia as DLTs. Methods: Patients (pts) with advanced solid tumors, PS ≤ 1, and ≤ 3 prior chemotherapy regimens were eligible for this study. Escalating doses of carboplatin (AUC 4-6) were administered over 30 minutes followed by a 1-hour infusion of escalating doses of ispinesib (9– 21 mg/m2) on a 21-day schedule. At least 3 pts were treated at each dose level. The primary objectives of this study included characterizing safety and tolerability and defining the optimally tolerated regimen (OTR). Limited pharmacokinetic (PK) samples were obtained. Clinical response assessments per RECIST criteria were performed every 2 cycles. Results: 24 pts [15 M/9 F; median age 63yrs, ECOG PS 1], were treated at 6 dose levels. The most common tumor types were prostate (7) and breast (4). A median of 3 cycles were administered (range 1–7; total 75 cycles). In 17 pts, the most common toxicities were (# pts, [grade]): nausea (10, Gr 1–2), vomiting (8, Gr 1–3), fatigue (8, Gr 1–2), neutropenia (8, Gr 2–4), anemia (7, Gr 1–3), and thrombocytopenia (7, Gr 1–4). Gr 4 thrombocytopenia was the observed DLT in 2 pts [ispinesib (mg/m2)/carboplatin (mg/ml·min) (# pts): 15/6 (1); 18/6 (1). PK assessment of ispinesib and carboplatin will be completed when the OTR has been defined. Unconfirmed minor responses have been observed in 3 pts (breast, prostate, NSCLC) starting at doses of 18/6. Conclusions: Determination of an OTR is ongoing. Ispinesib doses ≥ single agent MTD when combined with carboplatin AUC 6 have an acceptable tolerability profile and demonstrate preliminary evidence of anti-tumor activity. [Table: see text]

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.

A phase Ib/II study of olutasidenib in patients with relapsed/refractory IDH1 mutant solid tumors: Safety and efficacy as single agent.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16643-e16643
Author(s):  
Robin Lewis Jones ◽  
Teresa Macarulla ◽  
John A. Charlson ◽  
Brian Andrew Van Tine ◽  
Lipika Goyal ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Single Agent ◽  
Median Number ◽  
Clinical Activity ◽  
Tumor Type ◽  
Dna Hypermethylation ◽  
Efficacy Evaluation ◽  
Open Label ◽  
Isocitrate Dehydrogenase 1

e16643 Background: Isocitrate dehydrogenase 1 mutations (mIDH1) are present in a variety of solid tumors resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. Olutasidenib is an oral, potent and selective inhibitor of mutated IDH1 protein. We report preliminary results from the ongoing, first-in-human, Phase 1, open-label, single-arm study of olutasidenib in non-CNS solid tumors. Methods: Patients with advanced relapsed/refractory (R/R) mIDH1 solid tumors received olutasidenib 150 mg BID, orally. Following a dose confirmation cohort (Phase 1b), patients with intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma (CS), or unspecified mIDH1 solid tumors (Other) were enrolled in a Phase 2 efficacy evaluation (NCT: 03684811). Results: As of 31-Oct-2019, 44 patients with relapsed or refractory mIDH1 solid tumors were treated with olutasidenib. Diagnosis included: IHCC (n = 26), CS (n = 13), and Other (n = 5). The median age was 58 years (range: 29-81) and 43% were male. Median number of prior treatments was 2 (1-10). mIDH1 status was locally determined (IHC, NGS or PCR): R132C (61%), R132G (7%), R132S (7%), R132H (2%), R132L (2%), Others (2%) & unspecified (18%). Fourteen patients discontinued treatment (disease progression [n = 6; 3 IHCC, 2 CS, 1 Other], AE [n = 4; 3 IHCC, 1 CS], PI decision [n = 3; IHCC] & withdraw consent [n = 1; IHCC]). Treatment emergent adverse events (all grades, regardless of attribution) that occurred in > 15% of pts were: nausea (43%), fatigue (25%), decreased appetite (22%), AST increase (18%), ALT increase (16%), and constipation (16%). No protocol-defined DLTs occurred. Best responses by tumor type are shown in the table. Conclusions: Single agent olutasidenib at 150 mg BID demonstrates acceptable safety and tolerability with preliminary clinical activity in patients with R/R mIDH1 solid tumors. Updated safety and clinical activity, as well as exploratory evaluations of PK/PD will be provided. Clinical trial information: 03684811 . [Table: see text]

Targeted therapy for advanced solid tumors based on molecular profiles: Early results from MyPathway, an open-label, phase IIa umbrella basket study.

2016 ◽  
Vol 34 (18_suppl) ◽  
pp. LBA11511-LBA11511 ◽  
Author(s):  
John D. Hainsworth ◽  
Funda Meric-Bernstam ◽  
Charles Swanton ◽  
Herbert Hurwitz ◽  
David R. Spigel ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Solid Tumors ◽  
Current Response ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Curative Therapy ◽  
Molecular Alterations ◽  
Early Results ◽  
Open Label Phase ◽  
Tumor Types

LBA11511 Background: The MyPathway study (NCT02091141) evaluates agents targeting the HER2, BRAF, Hedgehog (Hh), or EGFR pathways in non-indicated tumors with relevant genetic abnormalities. Early results from MyPathway merit pre-planned tumor-cohort expansion. Methods: Eligible pts had advanced solid tumors with no curative therapy and molecular alterations in HER2, BRAF, Hh, or EGFR. Pts received standard doses of trastuzumab + pertuzumab (for the HER2 pathway), vemurafenib (BRAF), vismodegib (Hh), or erlotinib (EGFR) based on alteration. The primary endpoint is investigator-evaluated response rate within a tumor-pathway cohort (RECIST 1.1). Cohort size and expansion is determined by Simon’s two-stage design criteria. Results: By December 14, 2015, MyPathway included 129 pts with available baseline assessments and alterations in HER2 (n = 82; 53 amplifications, 23 mutations, 5 both, 1 RBMS-NRG1 fusion), BRAF (n = 33; 18 V600E, 15 other), Hh (n = 8; 7 PTCH1, 1 SMO), or EGFR (n = 6). Pts had a median of 3 (range, 0–10) prior lines of therapy. Best responses (n = 118) are shown below; 11 pts had insufficient follow-up for reevaluation and were not analyzed. 22 pts had PR/CR (1 CR); current response durations were up to 11 months. Conclusions: Targeted therapy produced responses in pts with 9 different tumor types outside of current drug indications. As enrollment increases for all tumor-pathway cohorts, analyses of tumor responses based on specific alterations (eg, HER2 amplifications vs. mutations) are planned. The HER2 amplified colorectal, bladder, and biliary, and the BRAF lung cohorts will be expanded based on observed activity. Clinical trial information: NCT02091141. [Table: see text]

A phase Ia/b study of TIM-3/PD-L1 bispecific antibody in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2654-TPS2654 ◽  
Author(s):  
Matthew David Hellmann ◽  
Toshio Shimizu ◽  
Toshihiko Doi ◽  
F. Stephen Hodi ◽  
Sylvie Rottey ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Checkpoint Inhibitors ◽  
Primary Objective ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Open Label Phase ◽  
Phase 1B

TPS2654 Background: Programmed cell death 1 immune checkpoint inhibitors (anti-PD-1, anti-PD-L1) have demonstrated clinical benefit in a subset of patients with manageable safety across a variety of tumor types. T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) can be co-expressed with PD-1 on exhausted T-cells and may be upregulated in tumors refractory to anti-PD-1 therapy (Koyama et al. 2016). Pre-clinical studies demonstrated that blockade of both PD-1 and TIM-3 improved survival of tumor-bearing mice compared to blocking anti-PD-1 only (Koyama et al. 2016). LY3415244 is a TIM-3/PD-L1 bispecific antibody that has the ability to target and inhibit both TIM-3 and PD-L1 and the potential to overcome primary and acquired anti-PD-(L)1 resistance by a novel mechanism to bridge TIM-3- and PD-L1-expressing cells. Methods: Study JZDA is a multicenter, nonrandomized, open-label, Phase 1a/1b study of LY3415244 in patients with advanced solid tumors. In Phase 1a, subjects with any tumor type who are either PD-(L)1 inhibitor-naïve or exposed are eligible. In Phase 1b, expansion cohorts are planned in subjects with PD-(L)1-experienced NSCLC, urothelial carcinoma, and melanoma. Patients with malignant mesothelioma are not required to have received prior anti-PD-(L)1 therapy. The primary objective is to assess safety and tolerability of LY3415244 and identify the recommended Phase 2 dose (RP2D) in Phase 1a (dose escalation). Safety and tolerability of the RP2D will be assessed in Phase 1b (dose expansion). The secondary objectives are to assess the pharmacokinetics of LY3415244 in Phase 1a/1b and assess early antitumor activity of LY3415244 in Phase 1b cohorts. Pre- and on-treatment biopsies will be obtained to explore potential biomarkers of response. During Phase 1a, dose escalation cohorts will proceed via a modified toxicity probability interval-2 (mTPI-2) design with a 1-cycle (28-day) dose-limiting toxicity (DLT) observation period. LY3415244 will be dosed intravenously every 2 weeks. Data from Phase 1a will determine the RP2D, which will be used for all cohorts in Phase 1b. The study is currently open to enrollment. Clinical trial information: NCT03752177.

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 study of PM14 in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3078-3078
Author(s):  
Maria Vieito ◽  
Santiago Ponce Aix ◽  
Luis G. Paz-Ares ◽  
Rastilav Bahleda ◽  
Christophe Massard ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Geometric Mean ◽  
Human Study ◽  
Fine Tuning ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Ecog Ps ◽  
Tumor Types

3078 Background: PM14 is a new chemical entity that forms DNA adducts which specifically inhibit RNA synthesis and block active transcription of protein-coding genes. Antitumor activity has been demonstrated in vitro in several cell lines (e.g. lung, kidney, prostate), and in vivo in mice bearing xenografted human-derived tumors (soft tissue sarcoma, small cell lung cancer, ovarian, gastric, breast and renal cancer). Methods: Open-label, dose-escalating, phase I trial of PM14 administered as a 3-hour infusion i.v. every 3 weeks (q3wk) in patients (pts) with advanced solid tumors, adequate organ function and ECOG PS score of 0-1. Two schedules were explored: Schedule A (Day 1 [D1], Day 8 [D8]) and Schedule B (D1). Results: 37 pts were treated (Schedule A/B: 28/9 pts). Baseline characteristics of pts (A/B): median age 56/47 years; male 57%/56%; ECOG PS 0: 57%/56%; median of prior lines (range): 3 (1-8)/4 (1-10). Most common tumor types (A + B): STS (n=7 pts), ovarian (n=6), pancreatic (n=4), prostate cancer (n=3). The maximum tolerated dose was 4.5 mg/m2 for A (dose-limiting toxicities [DLTs]: D8 omission due to lack of recovery of lab parameters for re-treatment [n=2 pts]) and 5.6 mg/m2 (DLTs: G4 febrile neutropenia [n=1], G4 transaminase increase [n=1]) for B. The recommended dose (RD) was 3.0 mg/m2 on D1,D8 (A), and 4.5 mg/m2 on D1 (B). No DLTs were present at the RDs. Most common toxicities were hematological abnormalities and transaminase increase. Main toxicities at the RDs are shown below. Antitumor activity comprised stable disease ≥4 months in 7 heavily pretreated pts (6 in A; 1 in B) at all dose levels. Linear pharmacokinetics were observed for PM14 at tested doses (0.25-5.6 mg/m²), with geometric mean (CV%) total plasma clearance 5.9 L/h (88%), volume of distribution 128 L (81%) and median (range) terminal half-life 15.9 h (7.5-34.3 h). Less than 1.6% of administered dose was recovered in urine. Conclusions: RDs were determined for two PM14 schedules in pts with advanced solid tumors. At the RDs, PM14 is well tolerated and has a manageable safety profile. An expansion phase in specific tumor types, with an optional Bayesian continual reassessment method for RD fine-tuning, is ongoing with both schedules.[Table: see text]

Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3005-3005
Author(s):  
Irene Brana ◽  
Geoffrey Shapiro ◽  
Melissa Lynne Johnson ◽  
Helena Alexandra Yu ◽  
Debbie Robbrecht ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Tyrosine Kinases ◽  
Evaluation Studies ◽  
Single Agent ◽  
Optimal Dose ◽  
Primary Objective ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
Sequencing Data ◽  
Open Label

3005 Background: SHP2 transduces signals from activated receptor tyrosine kinases to downstream pathways including MAPK. TNO155 is a selective, allosteric, oral inhibitor of SHP2. Methods: CTNO155X2101 (NCT03114319) is an ongoing first-in-human, open-label dose escalation/expansion trial of TNO155 in adults with advanced solid tumors. The primary objective is to characterize the safety and tolerability of TNO155 and identify regimen(s) for future study. Secondary assessments included pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy. Here we present data from TNO155 single agent escalation. Results: As of 10/26/2020, 118 patients received TNO155 in variable schedules: once (QD; 1.5–70 mg; n = 55) or twice daily (BID; 30–50 mg; n = 25) in a 2 weeks on/1 week off (2w/1w) cycle; or QD in a 3w/1w cycle (30–60 mg; n = 32), or continuously (40 or 50 mg QD; n = 6). The most common cancer diagnoses treated were colorectal (54%), gastrointestinal stromal tumor (16%), non-small cell lung (12%), and head & neck (8%). The median number of prior antineoplastic therapies was 4 (range 1–10). Overall 109 patients (92%) have discontinued study treatment, 94 (80%) for progressive disease and 6 (5%) for adverse events (AEs). TNO155 showed rapid absorption (median day 1 Tmax ̃1.1 hours), an effective median T½ of ̃34 hours, and near dose-proportional exposure at day 14 (power model: AUCτ beta = 1.09 [90% CI 1.02–1.16]). AEs were mostly Grade 1/2 and generally consistent with on-target effects of SHP2 inhibition. The most common treatment-related AEs (all grades) were increased blood creatine phosphokinase (n = 33, 28%), peripheral edema (n = 31, 26%), diarrhea (n = 31, 26%), and acneiform dermatitis (n = 27, 23%). The most common treatment-related Grade ≥3 AEs were decreased platelets (n = 5, 4%), increased aspartate aminotransferase, diarrhea, and decreased neutrophils (each n = 4, 3%). The best observed response was stable disease (SD) per RECIST 1.1, reported in 24 (20%) patients, with a median duration of SD of 4.9 months (range 1.7–29.3). Evidence of SHP2 inhibition, as measured by change in DUSP6 expression by qPCR in paired pre- vs. on-treatment tumor samples, was seen in the majority of patients treated with TNO155 doses ≥20 mg/day (≥25% reduction, 38/42 [90%]; ≥50% reduction, 25/42 [60%]). Analysis of tumor whole-transcriptome RNA sequencing data is ongoing. Conclusions: TNO155 shows favorable pharmacokinetic properties and promising early safety and tolerability data at doses with evidence of target inhibition. The optimal dose using several schedules is still under evaluation. Studies of TNO155 in combination with other agents, including nazartinib (mutant-selective EGFR inhibitor[i]), adagrasib (KRAS G12Ci), spartalizumab (anti-PD-1 antibody), ribociclib (CDK4/6i), and dabrafenib (BRAFi) with LTT462 (ERKi), are ongoing (NCT03114319, NCT04330664, NCT04000529, NCT04294160). Clinical trial information: NCT03114319.

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