Abstract CT191: Phase 1, first-in-human, dose-escalation study of oral TP-1287, a cyclin dependent kinase 9 (CDK9) inhibitor, in patients (pts) with advanced solid tumors (ASTs) (2022)

Abstract Background: CDK9 blockade inhibits tumor growth and progression by impairing key oncogene transcription. TP-1287 is an orally delivered phosphate prodrug of the CDK9 inhibitor alvocidib. Safety outcomes from dose escalation of a phase 1 study of TP-1287 in pts with ASTs (NCT03604783) are presented. Methods: Dose Escalation: Pts with metastatic/progressive ASTs refractory to/intolerant of established therapy received oral TP-1287 starting once daily for 14 of 21 days at 1 mg, until the 2nd dose level was reached, then twice daily (BID) for 14 of 21 days for subsequent cohorts, or continuous BID dosing for 28 days. Escalation was evaluated via a 3+3 design. Primary objectives: maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary objectives: pharmacokinetics, pharmacodynamics, and antitumor activity. Dose Expansion: Pts with locally advanced/metastatic sarcoma will be treated at the RP2D. Primary objective: objective response rate. Secondary objectives: progression-free survival and safety. Results: At data cutoff (September 15, 2021), 49 pts (mean age 64.0 [37.0-84.4] y; 57.1% male; 73.5% ECOG PS 1) were enrolled/treated with TP-1287 (Dose Escalation). Three pts experienced dose-limiting toxicities (DLTs) considered possibly or probably related to study drug; 1 in the 11-mg BID group (nausea) and 2 in the 16-mg BID group (fatigue; confusion, somnolence); all resolved without sequelae. In all, 48 pts (98.0%) experienced treatment-emergent adverse events (TEAEs), most commonly fatigue, nausea, and diarrhea; 27 (55.1%) experienced a Grade ≥3 TEAE (Table); 21 (42.9%) experienced a serious adverse event; and 7 (14.3%) died ≤30 days after receiving the last dose (all deaths were considered unrelated to study drug). The RP2D was 11 mg BID continuous dosing. Conclusions: The RP2D was established as 11 mg BID continuous dosing. The dose expansion cohort is open for enrollment. Table. Safety All Patients (N=49) Adverse Events, n (%) TEAE, any Grade TEAE, Grade ≥3 Any TEAE 48 (98.0) 27 (55.1) TEAEs in ≥2 pts (any grade) and in ≥1 pt (grade ≥3) Fatigue 23 (46.9) 1 (2.0) Nausea 23 (46.9) 0 Diarrhea 20 (40.8) 4 (8.2) Decreased appetite 17 (34.7) 0 Anemia 13 (26.5) 7 (14.3) Vomiting 13 (26.5) 0 Dyspnea 10 (20.4) 1 (2.0) Edema peripheral 10 (20.4) 1 (2.0) Back pain 8 (16.3) 0 Constipation 8 (16.3) 0 Hyponatremia 7 (14.3) 0 Dehydration 6 (12.2) 0 Disease progression 6 (12.2) 6 (12.2)a Abdominal pain 5 (10.2) 1 (2.0) Dizziness 5 (10.2) 0 Headache 5 (10.2) 0 Hypokalemia 5 (10.2) 2 (4.1) Urinary tract infection 5 (10.2) 0 Anxiety 4 (8.2) 0 Arthralgia 4 (8.2) 0 Depressed level of consciousness 4 (8.2) 0 Depression 4 (8.2) 0 Fall 4 (8.2) 0 Somnolence 4 (8.2) 1 (2.0) Weight decreased 4 (8.2) 0 Abdominal distension 3 (6.1) 0 AST increased 3 (6.1) 0 Asthenia 3 (6.1) 0 Cough 3 (6.1) 0 Hypotension 3 (6.1) 1 (2.0) Lethargy 3 (6.1) 0 Myalgia 3 (6.1) 0 Neck pain 3 (6.1) 0 Pyrexia 3 (6.1) 0 Abdominal discomfort 2 (4.1) 0 ALT increased 2 (4.1) 0 Ascites 2 (4.1) 0 Cancer pain 2 (4.1) 1 (2.0) Confusional state 2 (4.1) 1 (2.0) Dysgeusia 2 (4.1) 0 Dysphagia 2 (4.1) 0 Dysuria 2 (4.1) 0 Flatulence 2 (4.1) 0 Generalized edema 2 (4.1) 1 (2.0) Hematuria 2 (4.1) 1 (2.0) Hot flush 2 (4.1) 0 Hyperbilirubinemia 2 (4.1) 0 Hypercalcemia 2 (4.1) 0 Hypocalcemia 2 (4.1) 0 Hypoesthesia 2 (4.1) 0 Hypoxia 2 (4.1) 1 (2.0) Mental status changes 2 (4.1) 1 (2.0) Musculoskeletal chest pain 2 (4.1) 0 Nasal congestion 2 (4.1) 0 Neuropathy peripheral 2 (4.1) 0 Night sweats 2 (4.1) 0 Pain 2 (4.1) 2 (4.1) Pain in extremity 2 (4.1) 0 Tachycardia 2 (4.1) 0 Thrombocytopenia 2 (4.1) 0 Tumor pain 2 (4.1) 1 (2.0) Acute kidney injury 1 (2.0) 1 (2.0) Atrial fibrillation 1 (2.0) 1 (2.0) Blood alkaline phosphatase increased 1 (2.0) 1 (2.0) Chest pain 1 (2.0) 1 (2.0) Disseminated intravascular coagulation 1 (2.0) 1 (2.0) Hemoglobin decreased 1 (2.0) 1 (2.0) Hydronephrosis 1 (2.0) 1 (2.0) Hydroureter 1 (2.0) 1 (2.0) Hyperglycemia 1 (2.0) 1 (2.0) Hypertension 1 (2.0) 1 (2.0) Malignant pleural effusion 1 (2.0) 1 (2.0) Pericardial effusion 1 (2.0) 1 (2.0) Pleural effusion 1 (2.0) 1 (2.0) Respiratory failure 1 (2.0) 1 (2.0)b Seizure 1 (2.0) 1 (2.0)c Swelling 1 (2.0) 1 (2.0) Syncope 1 (2.0) 1 (2.0) Treatment-emergent SAEs, any Grade All Patients - Any SAE 21 (42.9) SAEs in ≥2 pts Disease progression 6 (12.2) Anemia 2 (4.1) aGrade 3, n=1; Grade 5, n=5. bGrade 5. cGrade 4. ALT, alanine aminotransferase; AST, aspartate aminotransferase; pts, patients; SAE, serious adverse event; TEAE, treatment-emergent adverse event. Citation Format: Nicholas J. Vogelzang, Ben George, Nissa Ashenbramer, William J. Edenfield, Donald Richards, Mitchell E. Gross, Gil D. Fine, Pablo Martinez. Phase 1, first-in-human, dose-escalation study of oral TP-1287, a cyclin dependent kinase 9 (CDK9) inhibitor, in patients (pts) with advanced solid tumors (ASTs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT191.