Phase I Studies of CBP501, a G2 Checkpoint Abrogator, as Monotherapy and in Combination with Cisplatin in Patients with Advanced Solid Tumors

• Published in: Clinical cancer research Vol. 17; no. 10; pp. 3431 - 3442
• Main Authors: SHAPIRO, Geoffrey I, TIBES, Raoul, FERNANDEZ, Cristian, SUTHERLAND, William, SATO, Hitoshi, PIERCEALL, William E, WEAVER, David, SLOUGH, Scott, WASSERMAN, Ernesto, KUFE, Donald W, VON HOFF, Daniel, KAWABE, Takumi, GORDON, Michael S, SHARMA, Sunil, WONG, Bryan Y, EDER, Joseph Paul, BORAD, Mitesh J, MENDELSON, David S, VOGELZANG, Nicholas J, BASTOS, Bruno R, WEISS, Glen J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.05.2011
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; cdc25 Phosphatases - administration & dosage; cdc25 Phosphatases - adverse effects; cdc25 Phosphatases - therapeutic use; Cisplatin - administration & dosage; Cisplatin - adverse effects; Disease Progression; Female; G2 Phase - drug effects; Genes, cdc - drug effects; Humans; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - pathology; Peptide Fragments - administration & dosage; Peptide Fragments - adverse effects; Peptide Fragments - therapeutic use; Pharmacology. Drug treatments; Tumors; Antineoplastic agent; Human; Solid tumor; Drug combination; Patient; Malignant tumor; Cisplatin; Alkylating agent; Treatment; Cell cycle; Phase I trial; G2 Phase; Advanced stage; Monotherapy; Control point; Cancer; Platinum II Complexes
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-10-2345

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.