Exelixis reports initial results from dose-escalation stage of QUARTZ-101 study

Exelixis announced initial results from the ongoing dose-escalation stage of QUARTZ-101, a phase 1 clinical trial evaluating XL102, a potent, selective, irreversible and orally bioavailable small molecule cyclin-dependent kinase 7, or CDK7, inhibitor, in patients with advanced solid tumors. The data are being presented on Thursday, December 8 during the poster session at 7:00 a.m. CST at the 2022 San Antonio Breast Cancer Symposium, or SABCS. QUARTZ-101 is enrolling patients with solid tumors that are confirmed to be inoperable, locally advanced, metastatic or recurrent. As of the September 7, data cutoff, 26 enrolled patients had been treated with single-agent oral XL102 at five dose levels: 20 mg once daily, 40 mg once daily, 80 mg once daily, 120 mg once daily and 40 mg twice daily. The most common types of cancer for patients enrolled were hormone receptor-positive breast cancer, pancreatic cancer and sarcoma. Median age was 63 years. Seventy-three percent of patients had an Eastern Cooperative Oncology Group score of 1, and 77% had received at least three prior lines of systemic anti-cancer therapy for metastatic disease. A pharmacokinetic analysis demonstrated rapid absorption of XL102 with a Tmax of 1-3 hours and an elimination half-life of 5-9 hours. At day 28, AUC0-24 was doubled with the 40 mg twice-daily dose level versus the 40 mg once-daily dose level, supporting twice-daily oral dosing. Target occupancy was exposure-dependent and prolonged relative to XL102 pharmacokinetics, consistent with covalent binding to CDK7. The median duration of exposure was 9.1 weeks. XL102 was well tolerated at the dose levels evaluated. Dose reductions and dose delays due to a treatment-emergent adverse event occurred in 8% and 35% of patients, respectively; rates were highest with the 80 mg once-daily dose. The most common reasons for discontinuation were radiographic progression, adverse events, lack of clinical benefit and patient request. The most common TEAEs of any grade were diarrhea, nausea, fatigue, anemia and vomiting. TEAEs were generally grade 1 or 2. In the cohort of patients receiving the 40 mg twice-daily dose, one patient experienced dose-limiting toxicity, which was reversible and led to full recovery. Other grade 3 TEAEs were anemia, ascites, blood alkaline phosphatase increased, fatigue, gastric varices, hyperkalemia, hypertension and hypokalemia. There were no grade 5 treatment-related adverse events. The maximum tolerated dose and recommended phase 2 dose have not yet been determined. As of data cutoff, no objective responses had been observed. Two patients with stable disease remain on study treatment as of the data cutoff: one with breast cancer and one with liposarcoma, with treatment durations of 46 and 45 weeks, respectively. One additional patient with breast cancer achieved durable stable disease as the best response and discontinued study treatment at 25 weeks. The efficacy of XL102 will be further evaluated in additional patients in the single-agent dose-escalation cohorts, in the tumor-specific cohort-expansion stage and in planned combination studies.