M. J. Borad

Inhibition of the hedgehog pathway in advanced basal-cell carcinoma.

BACKGROUNDnMutations in hedgehog pathway genes, primarily genes encoding patched homologue 1 (PTCH1) and smoothened homologue (SMO), occur in basal-cell carcinoma. In a phase 1 clinical trial, we assessed the safety and pharmacokinetics of GDC-0449, a small-molecule inhibitor of SMO, and responses of metastatic or locally advanced basal-cell carcinoma to the drug.nnnMETHODSnWe selected 33 patients with metastatic or locally advanced basal-cell carcinoma to receive oral GDC-0449 at one of three doses; 17 patients received 150 mg per day, 15 patients received 270 mg per day, and 1 patient received 540 mg per day. We assessed tumor responses with the use of Response Evaluation Criteria in Solid Tumors (RECIST), physical examination, or both. Molecular aspects of the tumors were examined.nnnRESULTSnThe median duration of the study treatment was 9.8 months. Of the 33 patients, 18 had an objective response to GDC-0449, according to assessment on imaging (7 patients), physical examination (10 patients), or both (1 patient). Of the patients who had a response, 2 had a complete response and 16 had a partial response. The other 15 patients had either stable disease (11 patients) or progressive disease (4 patients). Eight grade 3 adverse events that were deemed to be possibly related to the study drug were reported in six patients, including four with fatigue, two with hyponatremia, one with muscle spasm, and one with atrial fibrillation. One grade 4 event, asymptomatic hyponatremia, was judged to be unrelated to GDC-0449. One patient withdrew from the study because of adverse events. We found evidence of hedgehog signaling in tumors that responded to the treatment.nnnCONCLUSIONSnGDC-0449, an orally active small molecule that targets the hedgehog pathway, appears to have antitumor activity in locally advanced or metastatic basal-cell carcinoma. (ClinicalTrials.gov number, NCT00607724.)

Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors

Purpose: Bosutinib, a potent ATP-competitive, quinolinecarbonitrile Src/Abl kinase inhibitor, was tested in this first-in-human phase I trial in patients with advanced solid tumor malignancies. Patients and Methods: This trial was conducted in 2 parts. In part 1 (dose escalation), increasing oral bosutinib doses were administered using a 3 + 3 design. In part 2 (dose expansion), approximately 30 patients each with refractory colorectal, pancreas, or non–small cell lung cancer were treated at the recommended phase II dose (RP2D). Primary efficacy endpoints for part 2 were median progression-free survival (colorectal and non–small cell lung) and median overall survival (pancreas). Results: In part 1, dose-limiting toxicities of grade 3 diarrhea (two patients) and grade 3 rash occurred with bosutinib 600 mg/day and the maximum tolerated dose identified was 500 mg/day. However, the majority of patients treated with 500 mg/day had grade 2 or greater gastrointestinal toxicity, and 400 mg/day was identified as the RP2D. The most common bosutinib-related adverse events were nausea (60% patients), diarrhea (47%), vomiting (40%), fatigue (38%), and anorexia (36%). Bosutinib had a mean half-life of 19 to 20 hours at the RP2D. A partial response (breast) and unconfirmed complete response (pancreas) were observed; 8 of 112 evaluable patients had stable disease for 22 to 101 weeks. However, the primary efficacy endpoints for part 2 were not met. Conclusions: Bosutinib was generally well tolerated in patients with solid tumors, with the main toxicity being gastrointestinal. The RP2D was 400 mg/day orally. Further study of bosutinib is planned in combination regimens. Clin Cancer Res; 18(4); 1092–100. ©2011 AACR.

Abstract B47: CBP501, a novel cell cycle dysregulator, in combination with cisplatin (CDDP) and pemetrexed (PM) ‐ results of two phase I/II studies

Background: CBP501 is a synthetic peptide that appears to increase intracellular CDDP and enhance DNA damage caused by bleomycin and CDDP in cancer cells, which may lead to cell death. Activity has been identified in various tumor models. Previously it was determined that the MTD of single agent CBP501 was 25 mg/m2, with histamine release syndrome (HRS) as the dose limiting toxicity (DLT). Two clinical trials have evaluated CBP501 combinations, determining maximum tolerated dose (MTD), DLT, safety, activity and PK: Study A, phase I, CBP501 with CDDP; Study B, phase I/II, CBP501 with CDDP and PM. Both phase I studies were performed in patients (pts) with solid tumors. The phase II part of Study B is ongoing and will not be presented here. Materials and Methods: Eligibility criteria were standard. CBP501 was given i.v. over 1 hr via central or peripheral catheter, with prophylactic anti‐allergics for HRS. MTD was the level below that in which 2 of 3–6 pts had DLT during C1 and C2 for Study A, and C1 for Study B. Study A: q3w, initial CBP501/CDDP doses 3.6/50 mg/m2. Study B: q3w, initial CBP501/CDDP/PM doses 16/75/500 mg/m2. PK is reported separately. Results: The studies were conducted in 3 US centers from Nov‐06 to Aug‐09. 54 pts were included and treated. Study A) 48 pts in 7 dose levels: M/F 18/30; median age 61 (31–81); PS 0/1: 15/33; median number of prior lines 4 (0–14); primary site: ovarian (14 pts), mesothelioma (MST; 8), NSCLC (5), endometrial (4), prostate (4), other (13); total cycles (cy) administered 182 (median 4, range 1–13). Two DLTs (G3 HRS) occurred at CBP501/CDDP 36.4/75 mg/m2; the MTD was thus defined as 25/75 mg/m2. G3–4 toxicities included fatigue (4 pts), nausea (3), anemia (3), neutropenia (2), HRS (2), vomiting, QTc prolongation and renal failure (1 pt each). HRS was the most common AE, observed in 34 pts (70 %), but did not cause respiratory or hemodynamic problems. Efficacy: 3 confirmed partial responses (PR) were observed (2 platinum‐resistant ovarian pts, 1 pleural MST pt); 3 ovarian pts had CA‐125 responses. Sustained stable disease (SD) was observed in 5 ovarian pts (10, 9, 7, 5 and 4 cy), 2 pleural MST (13 and 5 cy), 1 neuroendocrine tumor pt (6 cy) and 1 salivary gland adenocarcinoma pt (9 cy). Study B) 6 pts to date, in 2 dose levels (16 and 25 mg/m2 CBP501) with fixed doses of CDDP/PM (75/500 mg/m2/): M/F: 5/1; median age 63 (37–74); PS 0/1: 1/5; primary site: mesothelioma (4 pts), ACUP (1), bladder (1); total cy administered 30 (median 5, range 1–9). No DLTs have been observed; the highest dose studied was defined as the RD for phase II studies. G3–4 related AEs were: DVT (2 pts), anemia (1 pt), syncope (1 pt) and fatigue and anorexia (1 pt). Anemia, fatigue and HRS were the most common AEs, in 6, 5 and 5 pts, respectively. Efficacy: PR was observed in 1 MST pt (9 cy), and SD in 3 MST pts (9, 5 and 4 cy). Conclusion: CBP501 appears to be well tolerated in combination with CDDP and CDDP/PM. The most frequent CBP501 toxicity was HRS, which is manageable. CBP501 did not enhance the expected toxicity of CDDP/PM. PR was seen in platinum‐resistant ovarian pts and MST pts. Two randomized phase II studies of CBP501/CDDP/PM are ongoing in pleural MST and NSCLC. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B47.

Clinical trial designs for more rapid proof-of-principle and approval

This chapter reviews and proposes clinical trial design innovations that will hopefully not only accelerate the drug development process, but also improve upon its success rate. The promise of more targeted, rationally designed drugs has unfortunately not resulted in more new agents being approved for routine clinical use. A recent review found that oncology is one of the worst therapeutic areas in terms of attrition rates. There are many compounds that have entered pivotal Phase III trials and subsequently have not been approved. Most prominent amongst these in terms of oncology drug development are biomarker development, streamlining clinical trials through novel designs, and the use of bioinformatics. Parallel to the FDAs Critical Path Initiative is the European Agency for the Evaluation of Medicinal Products (EMEA) initiative – the Innovative Medicines Initiative (IMI or InnoMed) –, which aims to foster public–private collaborations to accelerate drug development. In the battle against attrition for drug development in oncology, it may help to be armed with trial designs and techniques that can help not only to accelerate the process, but also to reduce the failure rate.

Concomitant medication (CM) use in phase I and II cancer clinical trials (CCT): Effects on trial eligibility and potential interactions with study medications.

6092 Background: CM use may result in ineligibility for CCT due to CM-study drug interactions, CM prolongation of QT interval, and alteration of study drug absorption by CM. Few studies have examin...