A phase I study of the multikinase inhibitor cabozantinib (C) plus docetaxel (D) and prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC).

Abstract

108 Background: Cabozantinib (C) is a multikinase inhibitor of c-Met, vascular endothelial growth factor receptor two and RET. C has shown activity in metastatic castrate resistant prostate cancer (mCRPC), with resolution of bone lesions on bone scan (BS), regression of soft tissue/visceral disease (STD), reductions in circulating tumor cells and bone biomarkers. Combining docetaxel (D) with other agents, without overlapping toxicities, can target different cellular signaling pathways necessary for tumor survival. Methods: Patients (pts), with no prior D for CRPC, receive a fixed dose of D (75 mg/m2 IV day one of each 21 day cycle) and prednisone (P) (5 mg po q12 hours) with C at three escalating dose levels: 20 mg, 40 mg, or 60 mg (all po daily). Using a standard three-plus-three design, three to six pts are treated at each dose level until the maximum tolerated dose (MTD) has been defined. Results: Thirteen pts have been accrued; four on dose level one, six on dose level two, and three on dose level three. Median age 69 (45 to 84). Four pts have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of zero and nine pts have a PS of one. Median Gleason score is nine (7 to 10). Median on-study prostate-specific antigen (PSA) is 129.2 ng/mL (0.01-508.5 ng/mL). Median cycles is six (1 to 17). Grade 1 adverse events (AEs), possibly related to C; dysgeusia (4/12), oral mucositis (4/12), increased ALT (3/12), and epistaxis (3/12). Grade 2 AEs; nausea (2/12), hand/foot syndrome (2/12), fatigue (2/12), dysgeusia (2/12), oral mucositis (2/12), hypophosphatemia (2/12), and anemia (2/12). Grade 3 AE is hypophosphatemia (2/12). Grade 4 AE is neutropenia (1/12). MTD of C is 60 mg. Of nine evaluable pts, six have bone only disease. Of these six, three pts have PSA declines of less than 30% with improvement on BS (two pts) or stable BS (one pt). The other three pts have PSA declines of greater than 30% and bone scan improvement. Three pts have STD and bone disease; one patient had a PSA decline of greater than 30% with improvement on BS and SD by CT scan. One patient had an increase in PSA of less than 30% with improvement on BS and CT. The third pt had PD by CT and an increase in PSA equal to 30%. PFS probability at six months is 90.0% and is 67.5% at eight months and beyond. Conclusions: The addition of C to D and P, has an acceptable toxicity profile. CT scan and BS improvements did not correlate with PSA declines in all pts. An expansion cohort will combine D plus P with C at the MTD (60 mg) to determine clinical benefit. Clinical trial information: NCT01683994.

Cabozantinib combination therapy for the treatment of solid tumors: a systematic review

“… 48 Two phase I/II studies demonstrated a clinical benefit of the combination with cabozantinib and prednisone (DP) compared with DP alone in patients with metastatic CRPC (mCRPC). 31 , 41 , 51 In addition, a phase Ib study showed clinically relevant activity with the combination of cabozantinib and atezolizumab in patients with mCRPC. 40 …”

“… 41 In the original phase I study, which included 13 patients receiving a combination of cabozantinib and DP, the probability of PFS was 90% at 6 months and 67.5% at 8 months. 51 …”

“…Among patients with mCRPC who received cabozantinib 40 mg with docetaxel in a phase I/II study, 31 , 41 , 51 DLTs were neutropenic fever and PPES, and there was one death due to a thromboembolic event. In addition, grade 3–4 myelosuppression, hypophosphatemia, and neuropathy were observed in at least three patients.…”

“…54 For prostate cancer, two studies investigated the triple combination therapy of cabozantinib plus DP in patients with CRPC and found positive results. 41,51 One of these was a randomized phase II study, which showed that cabozantinib plus DP was associated with longer PFS than DP in patients with CRPC. 41 In the expansion of the COSMIC-021 trial, which originally investigated cabozantinib and atezolizumab in RCC, preliminary data on the CRPC cohort have been encouraging, leading to the decision to expand this cohort further.…”

“…Three studies reported safety outcomes with cabozantinib in combination with three different chemotherapy drugs: a phase I/II study of cabozantinib plus docetaxel in patients with mCRPC; a phase I study of cabozantinib plus gemcitabine in patients with PDAC; and a phase I study of cabozantinib plus temozolomide in patients with high-grade gliomas (Table 3). 31,68,74 Among patients with mCRPC who received cabozantinib 40 mg with docetaxel in a phase I/II study, 31,41,51 DLTs were neutropenic fever and PPES, and there was one death due to a thromboembolic event. In addition, grade 3-4 myelosuppression, hypophosphatemia, and neuropathy were observed in at least three patients.…”