Phase I Studies of CBP501, a G(2) Checkpoint Abrogator, as Monotherapy and in Combination with Cisplatin in Patients with Advanced Solid Tumors
ABSTRACT Two phase I dose-escalation studies were conducted to determine the maximum tolerated dose (MTD) and safety profile of the G(2) checkpoint abrogator CBP501, as a single agent and in combination with cisplatin.
Patients with advanced solid tumors were treated with CBP501 alone (D1/D8/D15, q4w, from 0.9 mg/m(2)), or with cisplatin (both on D1, q3w, from 3.6 mg/m(2) CBP501, 50 mg/m(2) cisplatin). Dose escalation proceeded if dose-limiting toxicity (DLT) was observed in 1 or less of 3 to 6 patients; CBP501 dose increments were implemented according to the incidence of toxicity. MTD was determined from DLTs occurring during the first two cycles.
In the combination study, the DLT was a histamine-release syndrome (HRS) occurring 10 to 60 minutes after initiating infusion that was attenuated by prophylaxis comprising dexamethasone, diphenhydramine, ranitidine, and loratadine. The MTD was 25 mg/m(2) CBP501 and 75 mg/m(2) cisplatin, with two patients at the highest dose (36.4 mg/m(2) CBP501, 75 mg/m(2) cisplatin) experiencing grade 3 HRS. The only DLT with monotherapy was transient G(3) rise of troponin in one patient. Grade 3 to 4 treatment-related events were rare. Promising activity was observed with CBP501/cisplatin, mainly in ovarian and mesothelioma patients who had previously progressed on platinum-containing regimens. Among ovarian cancer patients, low expression of DNA repair proteins was associated with partial response or stable disease.
CBP501 is well tolerated in patients as monotherapy and with cisplatin. At the recommended phase II dose (RP2D), the combination is feasible and HRS manageable with prophylaxis. Evidence of antitumor activity was observed in platinum-resistant patients.
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ABSTRACT: Malignant pleural mesothelioma continues to challenge clinicians and scientists, since its incidence is rising and prognosis is far from favorable. Currently, the standard treatment consists of a combination of cisplatin and pemetrexed. The role of surgery and multimodality treatment remains controversial, while new treatment approaches, such as immunotherapy and targeted therapies, ad promising and interesting options. This review provides a comprehensive evaluation of emerging therapies and predictive biomarkers that are being tested.06/2012; 1(2). DOI:10.1007/s13665-012-0010-4
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ABSTRACT: CBP501 is an anti-cancer drug candidate that was investigated in two randomized Phase II clinical trials for patients with non-squamous non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). CBP501 has been shown to have two mechanisms of action, namely calmodulin modulation and G2 checkpoint abrogation. Here, we searched for a biomarker to predict sensitivity to CBP501. Twenty-eight NSCLC cell lines were classified into two subgroups, CBP501 sensitive and insensitive, by quantitatively analyzing the cis-diamminedichloro-platinum (II) (CDDP)-enhancing activity of CBP501 through treatments with short term (1h) co-exposure to CDDP and CBP501 or to either alone. Microarray analysis was performed on these cell lines to identify gene expression patterns that correlated with CBP501 sensitivity. We found that multiple Nuclear factor erythroid-2 related factor2 (Nrf2) target genes showed high expression in CBP501-insensitive cell lines. Western blot and immunocytochemical analysis for Nrf2 in NSCLC cell lines also indicated higher protein level in CBP501 insensitive cell lines. Moreover, CBP501 sensitivity is modulated by silencing or Sulforaphane (SFN) induced over-expression of Nrf2. These results indicate that Nrf2 transcription factor is a potential candidate as a biomarker for resistance to CBP501. This study might help to identify those subpopulations of patients who would respond well to the CBP501 and CDDP combination treatment for NSCLC.Molecular Cancer Therapeutics 07/2014; 13(9). DOI:10.1158/1535-7163.MCT-13-0808 · 5.60 Impact Factor
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ABSTRACT: Background CBP501, a synthetic duodecapeptide, increases cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and effects cell cycle progression by abrogating DNA repair at the G2 checkpoint. In Phase I clinical trials of CBP501 alone or in combination with cisplatin, the most common toxicity was infusion-related urticaria. Activity of CBP501 plus cisplatin was observed in patients with ovarian cancer and mesothelioma, including some patients previously treated with cisplatin. Methods Chemotherapy naïve patients with unresectable MPM were stratified by histology and performance status, and randomized 2:1 to pemetrexed/cisplatin plus CBP501 25 mg/m2 IV (Arm A) or pemetrexed/cisplatin alone (Arm B). The primary endpoint was progression free survival (PFS) at 4 months. Results 65 pts were randomized, and 63 were treated. Patient characteristics in the two arms were balanced. Based on independent radiology review of the treated population, 25/40 patients (63%) in Arm A and 9/23 (39%) in Arm B had PFS ≥ 4 mo; the median PFS was 5.1 mo (95% CI, 3.9, 6.5) versus 3.4 mo (2.5, 6.7). Median OS was 13.3 mo (9.2, 16.3) in Arm A and 12.8 (6.5, 16.1) in Arm B. Adverse events were no different than expected from standard chemotherapy, and comparable in the two arms, aside from infusion reactions which occurred in 70% of patients treated with CBP501. Conclusions While this randomized phase II trial met its primary endpoint of PFS at 4 months, other parameters such as response rate and overall survival suggest that the addition of CBP501 does not improve the efficacy of standard chemotherapy for MPM.Lung Cancer 09/2014; 85(3). DOI:10.1016/j.lungcan.2014.06.008 · 3.74 Impact Factor