The assumption of proportional hazard ratios is implicit in certain analyses of time-to-event endpoints such as Cox regression. Other statistical analyses, such as the nonparametric logrank test, possess some desirable properties only under the proportional hazards model. Data models for delayed effects of treatment on time-to-event endpoints such as survival violate the proportional hazards assumption.Fleming and Harrington's G ρ,γ class of weighted log-rank tests, a new option in SAS 9.1, is appropriate to test against a broad range of alternative hypotheses, including delayed treatment effects. A model for delayed treatment effects is proposed, and it is demonstrated that weighted log-rank tests are more powerful under this model than the standard unweighted log-rank test.
Standard frontline therapy for younger fit patients with newly diagnosed AML includes induction chemotherapy with continuous infusion cytarabine and an anthracycline (i.e., 7+3) with or without targeted agents such as midostaurin or gemtuzumab ozogamicin. However, overall outcomes are poor with 5-year survival rates <50%. Alvocidib is a cyclin-dependent kinase-9 (CDK9) inhibitor that leads to transcriptional suppression of MCL-1, an anti-apoptotic BCL-2 family member that is up-regulated in AML. Prior studies showed that alvocidib followed by cytarabine and mitoxantrone has anti-leukemic activity in both newly diagnosed and relapsed/refractory AML. This phase 1 study revealed that alvocidib 30 mg/m 2 IV over 30minutes followed by 60 mg/m 2 IV over 4-hours on days 1-3 can be administered prior to 7+3 induction in newly diagnosed AML patients with overall CR rates of 69% in patients with nonfavorable cytogenetics. Preliminary clinical activity was seen in secondary AML patients who have poor outcomes with conventional chemotherapy. Research.
Amuvatinib shows in vitro inhibitory activity against multiple human tyrosine kinases including mutant KIT and PDGFRα and in vivo activity in human xenograft models in mice. Amuvatinib is also active as a DNA repair protein Rad51 inhibitor following chemotherapy. In this study, the amuvatinib DPC formulation was well tolerated up to 1,500 mg/day. While exposures were low and variable, a transient response in a refractory GIST patient warrants further investigation into single-agent amuvatinib in refractory GIST.
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.
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