Dean Lim

A Phase II Trial of Vorinostat (Suberoylanilide Hydroxamic Acid) in Metastatic Breast Cancer: A California Cancer Consortium Study

Purpose: The primary goal of this trial was to determine the response rate of single-agent vorinostat in patients with metastatic breast cancer. The secondary goals included assessment of time to progression, evaluation of toxicities, and overall survival. Experimental Design: From June 2005 to March 2006, 14 patients received vorinostat, 200 mg p.o., twice daily for 14 days of each 21 day cycle. Response and progression were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results: The median age for all patients was 60.5 years (range, 37-88). Eight patients were estrogen receptor and/or progesterone positive, four were Her-2 positive. Sites of metastatic disease included brain, liver, lungs, bones, pelvis, pleura, chest wall, and distant lymph nodes. Patients received a median of 1.5 prior (range, 0-2) chemotherapeutic regimens for metastatic disease. Fatigue, nausea, diarrhea, and lymphopenia were the most frequent clinically significant adverse effects. The median number of cycles delivered was 2 (range, 1-20). There were no complete or partial responses, and the study was terminated after the first stage; however, 4 patients were observed with stable disease with time to progression of 4, 8, 9, and 14 months. The median number of months that patients received treatment on this study was 1.7 (range, 0.5-14). Conclusions: Although not meeting the RECIST response criteria for adequate single-agent activity, the observed tolerable toxicities and the potential for clinical benefit in terms of stable disease suggest that further assessment of vorinostat as a part of combination therapy with either chemotherapeutic or targeted agents in metastatic breast might be undertaken.

Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA

Significance CALAA-01 is a targeted nanoparticle containing siRNA that is a first-in-class experimental therapeutic for cancer. To our knowledge, it is the first targeted, polymer-based nanoparticle-carrying siRNA to be systemically administered to humans. Results from a human phase Ia/Ib clinical trial are presented and correlated to preclinical animal data to provide an initial assessment of how this class of experimental therapeutics is translated from animals to humans. Nanoparticle-based experimental therapeutics are currently being investigated in numerous human clinical trials. CALAA-01 is a targeted, polymer-based nanoparticle containing small interfering RNA (siRNA) and, to our knowledge, was the first RNA interference (RNAi)–based, experimental therapeutic to be administered to cancer patients. Here, we report the results from the initial phase I clinical trial where 24 patients with different cancers were treated with CALAA-01 and compare those results to data obtained from multispecies animal studies to provide a detailed example of translating this class of nanoparticles from animals to humans. The pharmacokinetics of CALAA-01 in mice, rats, monkeys, and humans show fast elimination and reveal that the maximum concentration obtained in the blood after i.v. administration correlates with body weight across all species. The safety profile of CALAA-01 in animals is similarly obtained in humans except that animal kidney toxicities are not observed in humans; this could be due to the use of a predosing hydration protocol used in the clinic. Taken in total, the animal models do appear to predict the behavior of CALAA-01 in humans.

Prognostic Indicators and Survival in Patients With Stage IIIB Inflammatory Breast Carcinoma After Dose-Intense Chemotherapy

PURPOSE To improve treatment outcome for patients presenting with inflammatory breast cancer (IBC), we have sequentially developed and tested single and tandem dose-intense chemotherapy regimens (DICT). Tumor- and treatment-related factors were analyzed to generate a prognostic model. PATIENTS AND METHODS Between May 1989 and April 2002, 120 patients received conventional-dose chemotherapy, surgery, and sequentially developed single- or tandem-cycle DICT. Disease- and treatment-specific features were subjected to univariate and multivariate analysis to correlate with outcome. RESULTS At a median follow-up of 61 months (range, 21 to 161 months), estimated 5-year relapse-free survival (RFS) and overall survival (OS) were 44% (95% CI, 34% to 53%) and 64% (95% CI, 55% to 73%), respectively. In an age-adjusted multivariate analysis, RFS was better in patients with estrogen receptor (ER)/progesterone receptor (PR)-positive tumors (P =.002), for patients with fewer than four involved axillary nodes before DICT (P =.01), and in patients treated with radiation therapy (P =.001) and tandem DICT (P =.049). OS was improved in patients with ER/PR-positive tumors (P =.002), in those with fewer than four involved axillary nodes before DICT (P =.03), and in patients treated with radiation therapy (P =.002). CONCLUSION This retrospective analysis suggests that either single or tandem DICT can be administered safely and may benefit selected patients with stage IIIB IBC. Those with receptor-negative IBC and with four or more involved axillary nodes before DICT need improved neoadjuvant and postadjuvant intensification therapy. A prospective randomized trial of single versus tandem DICT would be required to confirm the potential benefit of tandem DICT in the setting of IBC.

Phase I trial of intraperitoneal gemcitabine in the treatment of advanced malignancies primarily confined to the peritoneal cavity

Purpose: To determine the maximally tolerated dose, toxicity, and pharmacokinetics of i.p. gemcitabine. Experimental Design: Patients had peritoneal carcinomatosis. Gemcitabine (40, 80, 120, or 160 mg/m2) was administered into the peritoneal cavity in 2 L of warmed saline on days 1, 4, 8, and 12 of a 28-day cycle. Results: Thirty patients received 63 (median, 2; range, 0-6) courses. Tumors included ovary (14), uterus (2), colon (6), pancreas (3), and others (5). Dose-limiting toxicity included nausea, vomiting, diarrhea, dyspnea, fatal respiratory failure, and grade 3 elevation of alanine aminotransferase in three patients. Hematologic toxicity and pain were ≤grade 2. Three patients had decreased or resolved ascites. Of 19 patients evaluable for response, 10 had stable disease (median, 3.5 courses) and 9 had progressive disease. The median peak peritoneal concentration was 1,116-fold (range, 456-1,886) higher than the peak plasma level. Plasma and peritoneal levels were undetectable within 8 to 12 h. At 120 mg/m2, the median peritoneal area under the concentration versus time curve (AUC) was 82,612 ng/mL × h (range, 53,296-199,830) and the plasma AUC was 231 ng/mL × h (range, 47.6-259.5). The mean peritoneal advantage (AUCperitoneal/AUCplasma) was 847 (range, 356-1,385). Conclusions: I.p. administration of gemcitabine is tolerated within the tested dosage range. Technical problems with the Porta-Cath device and i.p. therapy per se may have been exacerbated by the enrollment of many patients with a variety of advanced i.p. diseases. Given the significant increase in local dose intensity and the documented activity of this drug, this agent may be an excellent candidate for i.p. therapy in optimally debulked ovarian cancer, either alone or in combination.

Phase I trial of menadiol diphosphate (vitamin K3) in advanced malignancy.

SummaryBased on the activity of menadione (M) in the human tumor stem cell assay, we conducted a phase I trial of M in patients with advanced cancer. Forty patients (19 men, 21 women) were treated with 90 courses of M; 82 treatment courses are evaluable for toxicity. The median patient age, Karnofsky performance status, and number of prior chemotherapy regimens were 61 years (range 32–74 years), 80% (range 50–100%), and two, respectively. M was given by a short (1–5 h) intravenous infusion every 3 weeks, starting at 40 mg/m2 and escalating by modified Fibonacci scheme to 1360 mg/m2. Toxicity was graded according to the Southwest Oncology Group toxicity scale with defined hypersensitivity reaction (HSR) scales. No grade ≧2 hematologic toxicity was observed. Non-hematologic toxicity consisted of a HSR syndrome of paresthesiae of the extremities, facial flushing, burning of the eyes and mucous membranes, chest pain and dyspnea. HSR was defined as Grade I toxicity by the presence of facial numbness, flushing, and/or a tingling sensation or burning of the eyes and mucous membranes. Grade II toxicity was defined as the presence of the same above symptoms plus chest tightness, paresthesiae of extremities and/or dyspnea and chest pain. These toxicities were grade 1 in 3 of 4 patients at a dose of 840 mg/m2. At 1360 mg/m2, 2 of 13 patients suffered grade 1 HSR and 7 of 13 grade 2 HSR No objective partial or complete responses were observed. Plasma menadione concentrations peaked at 1.9–7.4 μ M during the infusion in 3 patients receiving 1360 mg/m2. Further phase 1 and 2 combination trials using longer infusion durations have resulted from this trial.

Phase I study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors.

Background:Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours.Methods:Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7–1.4 mg m−2 and CP 60–75 mg m−2. Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m−2, CP 60 mg m−2) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days.Results:On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m−2, 60 mg m−2); G 3 anorexia/fatigue/hypokalemia (1.2 mg m−2, 60 mg m−2); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m−2, 60 mg m−2). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m−2, 60 mg m−2); G 4 mucositis (1.4 mg m−2, 60 mg m−2); and G 3 hypokalemia (1.2 mg m−2, 75 mg m−2). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m−2 (days 1, 8) and CP 75 mg m−2 (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers).Conclusions:On the 21-day cycle, eribulin mesylate 1.2 mg m−2, administered on days 1 and 8, in combination with CP 75 mg m−2, administered on day 1 is well tolerated and showed preliminary anticancer activity.

Panitumumab following disease progression on cetuximab in patients with metastatic colorectal cancer: A retrospective review

Despite advances in treatment options for metastatic colorectal cancer over the past decade, the number of chemotherapy agents available remains limited. We report here a retrospective review of 11 patients who were treated with panitumumab following documented disease progression on cetuximab. Two patients demonstrated minor radiographic responses, albeit only for a short period of time. We conclude that the use of one epidermal growth factor receptor inhibitor following failure on the other may be of benefit to patients who would otherwise have no other treatment options. However, studies to help identify the subset of patients who might benefit from this strategy are needed.

A phase I clinical trial of binimetinib in combination with FOLFOX in patients with advanced metastatic colorectal cancer who failed prior standard therapy

BACKGROUND This was a first in-human, open-label, dose-escalation phase I study conducted to evaluate the maximum tolerated dose (MTD), safety, and efficacy of the combination of oral binimetinib and FOLFOX. MATERIALS AND METHODS Patients with metastatic colorectal cancer (mCRC) who progressed on prior standard therapies received twice daily binimetinib continuously or intermittently with FOLFOX. Dose-limiting toxicities (DLTs) were assessed in the first 2 cycles of study treatment. Pharmacokinetic (PK) analysis of 5-FU and oxaliplatin was performed at the MTD in an expanded 6 patient cohort. RESULTS Twenty-six patients were enrolled and assessed for safety. In the dose-escalation phase, no DLTs were noted in all binimetinib dosing schedules and the MTD of binimetinib in with FOLFOX was 45 mg orally twice daily. There were no significant differences in the PKs of 5-FU or oxaliplatin with or without binimetinib. Continuous dosing of binimetinib produced SD at 2 months in 9 of 13 evaluable patients and a median PFS of 3.5 months. Nine of 10 patients had PD at 2 months on the intermittent arm. CONCLUSIONS Oral binimetinib and FOLFOX has a manageable toxicity profile and showed some evidence of antitumor activity in heavily pretreated mCRC patients.Background This was a first in-human, open-label, dose-escalation phase I study conducted to evaluate the maximum tolerated dose (MTD), safety, and efficacy of the combination of oral binimetinib and FOLFOX. Materials and Methods Patients with metastatic colorectal cancer (mCRC) who progressed on prior standard therapies received twice daily binimetinib continuously or intermittently with FOLFOX. Dose-limiting toxicities (DLTs) were assessed in the first 2 cycles of study treatment. Pharmacokinetic (PK) analysis of 5-FU and oxaliplatin was performed at the MTD in an expanded 6 patient cohort. Results Twenty-six patients were enrolled and assessed for safety. In the dose-escalation phase, no DLTs were noted in all binimetinib dosing schedules and the MTD of binimetinib in with FOLFOX was 45 mg orally twice daily. There were no significant differences in the PKs of 5-FU or oxaliplatin with or without binimetinib. Continuous dosing of binimetinib produced SD at 2 months in 9 of 13 evaluable patients and a median PFS of 3.5 months. Nine of 10 patients had PD at 2 months on the intermittent arm. Conclusions Oral binimetinib and FOLFOX has a manageable toxicity profile and showed some evidence of antitumor activity in heavily pretreated mCRC patients.

Phase Ib Trial of mFOLFOX6 and Everolimus (NSC-733504) in Patients with Metastatic Gastroesophageal Adenocarcinoma

Objectives: Based upon preclinical data showing synergy with mTOR inhibition and platinum chemotherapy, this study explores the safety and tolerability of combining everolimus with mFOLFOX6 for patients with metastatic gastroesophageal adenocarcinoma. Methods: Eligible patients with metastatic gastroesophageal adenocarcinoma received standard-dose mFOLFOX6 chemotherapy in combination with escalating doses of everolimus. Results: Six patients were accrued to the first dose level of 2.5 mg everolimus daily with mFOLFOX6. Overall, the toxicity profile was manageable with expected grade 3 toxicities of mucositis and neutropenia. The dose-limiting toxicity (DLT) included a week delay in therapy greater than 7 days as a result of the first 2 courses of mFOLFOX6. Two patients experienced DLTs at the first dose level due to delays in their treatment caused by prolonged grade 2 neutropenia and fever with fatigue. They were allowed to continue with a dose reduction of their chemotherapy. The median overall survival and progression-free survival were 20.3 and 14.5 months, respectively. Conclusions: The combination of mFOLFOX6 and everolimus is an active regimen with 83% of the patients experiencing a partial response. p53 mutations were found in the 5 samples analyzed.

Pilot trial of CRLX101 in patients with advanced, chemotherapy-refractory gastroesophageal cancer

Background CRLX101 is an investigational nanoparticle-drug conjugate with a camptothecin payload. Preclinical evidence indicated preferential uptake in tumors, and tumor xenograft models demonstrate superiority of CRLX101 over irinotecan. A pilot trial was conducted at recommended phase 2 dosing (RP2D) using the bimonthly schedule to assess preferential uptake of CRLX101 in tumor vs. adjacent normal tissue in endoscopically accessible tumors in chemotherapy-refractory gastroesophageal cancer. Results from the biopsies were previously reported and herein we present the clinical outcomes. Methods Patients initiated CRLX101 dosed at RP2D (15 mg/m2) on days 1 and 15 of a 28-day cycle. Detection of preferential CRLX101 tumor uptake was the primary endpoint and objective response rate (ORR) was a secondary endpoint. With a sample size of ten patients, the study had 90% power to detect ≥1 responder if the true response rate is ≥21%. Results Between Dec. 2012 and Dec. 2014, ten patients with chemotherapy-refractory (median 2 prior lines of therapy, range 1-4) gastric adenocarcinoma were enrolled. The median time-to-progression was 1.7 months. Best response was seen in one patient with stable disease (SD) for 8 cycles. Only ≥ grade 3 drug-related toxicity occurred in one patient with grade 3 cardiac chest pain who was able to resume therapy after CRLX101 was reduced to 12 mg/m2. Conclusions Bimonthly CRLX101 demonstrated minimal activity with SD as best response in this heavily pretreated population. Future efforts with CRLX101 in gastric cancer should focus on combination and more dose-intensive strategies given its favorable toxicity profile and evidence of preferential tumor uptake.