2619 Background: The 90kDa heat shock protein (HSP90) participates in the folding, stabilization, activation, and proteolytic turnover of aberrant proteins that contribute to the growth and survival of cancer cells. HSP90 inhibition leads to degradation of these aberrant proteins through the ubiquitin-proteosome pathway, allowing for simultaneous targeting of multiple pathways. Inhibition of HSP90 alone stimulates a compensatory upregulation of HSP70. The transcriptional induction of HSP70 has been linked to the activity of CDK9. Combined inhibition of onalespib-mediated HSP90 inhibition and AT7519-mediated CDK9 inhibition has demonstrated synergistic anti-tumor activity in preclinical models at NOAEL doses, justifying a Phase 1 study. Methods: We conducted an open-label phase 1 study following a 3+3 trial design. Patients received a 1-week lead-in of onalespib alone (C0), followed by onalespib/AT7519M on days 1,4,8, and 11 of a 21-day cycle. Pharmacokinetic samples were obtained on C0D1 after onalespib alone, and on C1D1 and D11 with the combination. HSP70 protein levels were analyzed in PBMC and plasma samples collected at baseline, after onalespib alone, and after the combination, in order to demonstrate AT7519-mediated suppression of HSP70 expression. Patients enrolled to the expansion phase underwent optional paired tumor biopsies for assessment of proof-of-mechanism demonstration of modulation of client proteins. Results: Twenty-eight patients have been treated, 10 of whom were enrolled to the expansion cohort with optional tumor biopsies. The MTD is DL2: onalespib 80 mg/m2 IV + AT7519M 21 mg/m2 IV on days 1,4,8, and 11 of a 21-day cycle. At DL3, DLTs included Grade 3 troponin elevation and mucositis. Drug-related adverse events occurring in ≥ 30% of patients include diarrhea, fatigue, mucositis, nausea, and vomiting, consistent with known toxicities of these agents. Two patients with colorectal and endometrial cancer, respectively, remained on study for 10 cycles with SD as the best response. Modulation of HSP70 were demonstrated in patient plasma samples. Conclusions: The combination of onalespib and AT7519 is tolerable, although the doses of both agents were below the monotherapy MTDs. Prolonged disease stabilizations were observed. Pharmacokinetic and pharmacodynamic analyses are ongoing, including assessment of HSP70 expression in plasma and tumor. Clinical trial information: NCT02503709.
A Phase 1 study of
GDC
‐0134, a dual leucine zipper kinase inhibitor, in
ALS
