Phase I study of cediranib, an oral VEGFR inhibitor, in combination with selumetinib, an oral MEK inhibitor, in patients with advanced solid malignancies.

PURPOSE: Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response. METHODS: Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length. RESULTS: Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients. CONCLUSIONS: Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib.

Randomized Phase II Trial of Capecitabine and Lapatinib with or without IMC-A12 (Cituxumumab) in Patients with HER2-Positive Advanced Breast Cancer Previously Treated with Trastuzumab and Chemotherapy: NCCTG N0733 (Alliance).

PURPOSE: To compare efficacy and safety of capecitabine and lapatinib with or without IMC-A12 (cituxumumab) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab. PATIENTS AND METHODS: Following an initial safety run-in cohort, patients were randomized 1:2 to Arm A (capecitabine and lapatinib) or to Arm B (capecitabine, lapatinib, and cituxumumab). Given the frequency of non-hematologic grade ≥ 3 adverse events in those receiving the three-drug combination in the safety cohort, lapatinib and capecitabine doses were reduced in Arm B only. The primary objective was to determine if the addition of cituxumumab to capecitabine and lapatinib improved progression-free survival (PFS) compared with capecitabine and lapatinib. Secondary objectives included a comparison between arms of other clinical endpoints, safety, change in overall quality of life (QOL) and self-assessed fatigue, rash, diarrhea, and hand-foot syndrome. RESULTS: From July 2008 to March 2012, 68 patients (out of 142 planned) were enrolled and 63 were evaluable, including 8 for the safety run-in and 55 for the randomized cohort. Study enrollment was stopped early due to slow accrual. The addition of cituxumumab to capecitabine and lapatinib did not improve PFS (HR 0.93, 95% CI: 0.52-1.64). Furthermore, no difference in objective response rate or overall survival (OS) was observed. No difference between arms was observed in grade ≥ 3 adverse events, overall QOL change from baseline after 4 cycles of treatment. CONCLUSION: The addition of cituxumumab to lapatinib and capecitabine did not improve PFS or OS compared with lapatinib and capecitabine in patients with HER2-positive MBC. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT00684983.

Phase 1 trial of Vismodegib and Erlotinib combination in metastatic pancreatic cancer.

BACKGROUND/OBJECTIVES: Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating the outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting of these pathways may be clinically beneficial. This Phase I study combined HH and EGFR inhibition in metastatic PDAC patients. METHODS: Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers. RESULTS: Treatment was well tolerated with the maximum tolerated dose cohort experiencing no grade 4 toxicities though 25% experienced grade 3 adverse effects. Recommended phase II dose of Vismodegib and Erlotinib were each 150 mg daily. No tumor responses were observed although 16 patients achieved stable disease for 2-7 cycles. Paired biopsy analysis before and after first cycle of therapy in PDAC patients showed reduced GLI1 mRNA, phospho-GLI1 and associated HH target genes in all cases. However, only half of the cases showed reduced levels of desmoplasia or changes in fibroblast markers. Most patients had decreased phospho-EGFR levels. CONCLUSIONS: Vismodegib and Erlotinib combination was well-tolerated although overall outcome in patients with metastatic PDAC was not significantly impacted by combination treatment. Biomarker analysis suggests direct targets inhibition without significantly affecting the stromal compartment. These findings conflict with pre-clinical mouse models, and thus warrant further investigation into how upstream inhibition of these pathways is circumvented in PDAC.

Phase 2 trial of everolimus and letrozole in relapsed estrogen receptor-positive high-grade ovarian cancers.

OBJECTIVES: We report the results of a phase 2 clinical trial of the combination of everolimus and letrozole in patients with relapsed estrogen receptor-positive high-grade ovarian cancer. The trial's primary endpoint was the proportion of patients alive and progression-free after 12weeks of therapy with the combination of everolimus and letrozole. A 12-week PFS of 45% or greater was considered a positive result. The feasibility of generating patient-derived xenograft (PDX) models from biopsy specimens was also evaluated. METHODS: Eligibility criteria included relapsed estrogen receptor-positive ovarian, fallopian tube or primary peritoneal carcinomas with measurable disease, not previously treated with everolimus or AIs. Both platinum-resistant and sensitive tumors were included. Xenografts were created from image-guided tumor biopsies at baseline. Patients received oral everolimus 10mg daily and letrozole 2.5mg daily. RESULTS: Twenty patients were enrolled, 19 were evaluable. Nine out of 19 were alive, progression-free, and still on treatment at the 12week evaluation time-point (12-week PFS of 47%) with a median PFS of 3.9months (95% CI: 2.8-11.0). The median overall survival was 13.0months. Twelve patients (63%) experienced at least one grade 3 or worse adverse events. PDX tumor engraftment was feasible in the majority of patients (9 out of 17, 52.9%). CONCLUSIONS: The combination of everolimus and letrozole is associated with a promising 47% 12-week PFS rate in patients with ER-positive relapsed high-grade ovarian cancer with acceptable toxicity. PDX tumor models can be generated from biopsies of ovarian tumors.

Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer.

BACKGROUND: Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth factor (IGF) pathway, the mTOR complex (mTORC1) mediates IGF-1 receptor (IGF-1R)-induced estrogen receptor alpha (ERα) phosphorylation/activation and leads to increased proliferation and growth in breast cancer cells. As a result, the prevalence of mTOR inhibitors combined with hormonal therapy has increased in recent years. Conversely, activated mTORC1 provides negative feedback regulation of IGF signaling via insulin receptor substrate (IRS)-1/2 serine phosphorylation and subsequent proteasomal degradation. Thus, the IGF pathway may provide escape (e.g. de novo or acquired resistance) from mTORC1 inhibitors. It is therefore plausible that combined inhibition of mTORC1 and IGF-1R for select subsets of ER-positive breast cancer patients presents as a viable therapeutic option. METHODS: Using hormone-sensitive breast cancer cells stably transfected with the aromatase gene (MCF-7/AC-1), works presented herein describe the in vitro and in vivo antitumor efficacy of the following compounds: dalotuzumab (DALO; "MK-0646"; anti-IGF-1R antibody), ridaforolimus (RIDA; "MK-8669"; mTORC1 small molecule inhibitor) and letrozole ("LET", aromatase inhibitor). RESULTS: With the exception of MK-0646, all single agent and combination treatment arms effectively inhibited xenograft tumor growth, albeit to varying degrees. Correlative tissue analyses revealed MK-0646 alone and in combination with LET induced insulin receptor alpha A (InsR-A) isoform upregulation (both mRNA and protein expression), thereby further supporting a triple therapy approach. CONCLUSION: These data provide preclinical rationalization towards the combined triple therapy of LET plus MK-0646 plus MK-8669 as an efficacious anti-tumor strategy for ER-positive breast tumors.

High expression of orphan nuclear receptor NR4A1 in a subset of ovarian tumors with worse outcome.

OBJECTIVE: Nuclear receptors (NRs) play a vital role in the development and progression of several cancers including breast and prostate. Using TCGA data, we sought to identify critical nuclear receptors in high grade serous ovarian cancers (HGSOC) and to confirm these findings using in vitro approaches. METHODS: In silico analysis of TCGA data was performed to identify relevant NRs in HGSOC. Ovarian cancer cell lines were screened for NR expression and functional studies were performed to determine the significance of these NRs in ovarian cancers. NR expression was analyzed in ovarian cancer tissue samples using immunohistochemistry to identify correlations with histology and stage of disease. RESULTS: The NR4A family of NRs was identified as a potential driver of ovarian cancer pathogenesis. Overexpression of NR4A1 in particular correlated with worse progression free survival. Endogenous expression of NR4A1 in normal ovarian samples was relatively high compared to that of other tissue types, suggesting a unique role for this orphan receptor in the ovary. Expression of NR4A1 in HGSOC cell lines as well as in patient samples was variable. NR4A1 primarily localized to the nucleus in normal ovarian tissue while co-localization within the cytoplasm and nucleus was noted in ovarian cancer cell lines and patient tissues. CONCLUSIONS: NR4A1 is highly expressed in a subset of HGSOC samples from patients that have a worse progression free survival. Studies to target NR4A1 for therapeutic intervention should include HGSOC.

In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma.

OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo. METHODS: Massively parallel sequencing was performed on HGSOCs to identify mutations contributing to HR deficiency. HR pathway integrity was assessed using fluorescence microscopy-based RAD51 focus formation assays. Effects of niraparib (MK-4827) on treatment-naïve PDX tumor growth as monotherapy, in combination with carboplatin/paclitaxel, and as maintenance therapy were assessed by transabdominal ultrasound. Niraparib responses were correlated with changes in levels of poly(ADP-ribose), PARP1, and repair proteins by western blotting. RESULTS: Five PDX models were evaluated in vivo. Tumor regressions were induced by single-agent niraparib in one of two PDX models with deleterious BRCA2 mutations and in a PDX with RAD51C promoter methylation. Diminished formation of RAD51 foci failed to predict response, but Artemis loss was associated with resistance. Niraparib generally failed to enhance responses to carboplatin/paclitaxel chemotherapy, but maintenance niraparib therapy delayed progression in a BRCA2-deficient PDX. CONCLUSIONS: Mutations in HR genes are neither necessary nor sufficient to predict response to niraparib. Assessment of repair status through multiple complementary assays is needed to guide PARP inhibitor therapy, design future clinical trials and identify ovarian cancer patients most likely to benefit from PARP inhibition.

North Central Cancer Treatment Group/Alliance trial N08CA-the use of glutathione for prevention of paclitaxel/carboplatin-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled study.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of taxane and platinum-based chemotherapy. Several studies have supported the potential benefit of glutathione for the prevention of platinum-induced CIPN. The current trial was designed to determine whether glutathione would prevent CIPN as a result of carboplatin/paclitaxel therapy. METHODS: In total, 185 patients who received treatment with paclitaxel and carboplatin were accrued between December 4, 2009 and December 19, 2011. Patients were randomized to receive either placebo (n = 91) or 1.5 g/m(2) glutathione (n = 94) over 15 minutes immediately before chemotherapy. CIPN was assessed using the European Organization for Research and Treatment of Cancer Quality-of-Life (EORTC-QLQ) 20-item, CIPN-specific (CIPN20) sensory subscale and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. RESULTS: There were no statistically significant differences between the 2 study arms with regard to: 1) peripheral neurotoxicity, as assessed using both the EORTC-QLQ-CIPN20 (P = .21) and the CTCAE scales (P = .449 for grade ≥2 neurotoxicity; P = .039 for time to development of grade ≥2 neuropathy, in favor of the placebo); 2) the degree of paclitaxel acute pain syndrome (P = .30 for patients who received paclitaxel every 3-4 weeks and P = .002, in favor of the placebo, for patients who received weekly paclitaxel); 3) the time to disease progression (P = .63); or 4) apparent toxicities. Subgroup analyses did not reveal any evidence of benefit in any particular subgroup. CONCLUSIONS: The results from this study do not support the use of glutathione for the prevention of paclitaxel/carboplatin-induced CIPN.

A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.

OBJECTIVE: Vascular endothelial growth factor (VEGF) receptor-mediated signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression is associated with poor clinical outcomes. We investigated ramucirumab, a fully human anti-VEGFR-2 antibody, in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Primary endpoints were progression-free survival at 6 months (PFS-6) and confirmed objective response rate (ORR). METHODS: Women who received ≥ 1 platinum-based chemotherapeutic regimen and had a platinum-free interval of <12 months with measurable disease were eligible. Patients received 8 mg/kg ramucirumab intravenously every 2 weeks. RESULTS: Sixty patients were treated; one patient remained on study as of September 2013. The median age was 62 years (range: 27-80), and median number of prior regimens was 3. Forty-five (75%) patients had platinum refractory/resistant disease. Thirty-nine patients (65.0%) had serous tumors. PFS-6 was 25.0% (n=15/60, 95% CI: 14.7-37.9%). Best overall response was: partial response 5.0% (n=3/60), stable disease 56.7% (n=34/60), and progressive disease 33.3% (n=20/60). The most common treatment-emergent adverse events possibly related to study drug were headache (65.0%; 10.0% Grade ≥ 3), fatigue (56.7%; 3.3% Grade ≥ 3), diarrhea (28.3%; 1.7% Grade ≥ 3), hypertension (25.0%; 3.3% Grade ≥ 3), and nausea (20.0%; no Grade ≥ 3). Two patients experienced intestinal perforations (3.3% Grade ≥ 3). Pharmacodynamic analyses revealed changes in several circulating VEGF proteins following initial ramucirumab infusion, including increased VEGF-A, PlGF and decreased sVEGFR-2. CONCLUSIONS: Although antitumor activity was observed, the predetermined efficacy endpoints were not met.

A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer.

The mammalian target of rapamycin (mTOR) plays a critical role in promoting tumor cell growth and is frequently activated in breast cancer. In preclinical studies, the antitumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated in part by Insulin-like growth factor type 1 receptor (IGF-1R). We designed a phase I trial to determine the maximum-tolerated dose (MTD) and pharmacodynamic effects of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer refractory to standard therapies. A 3 + 3 Phase I design was chosen. Temsirolimus and Cixutumumab were administered intravenously on days 1, 8, 15, and 22 of a 4-week cycle. Of the 26 patients enrolled, four did not complete cycle 1 because of disease progression (n = 3) or comorbid condition (n = 1) and were replaced. The MTD was determined from the remaining 22 patients, aged 34-72 (median 48) years. Most patients (86 %) had estrogen receptor positive cancer. The median number of prior chemotherapy regimens for metastatic disease was 3. The MTD was determined to be Cixutumumab 4 mg/kg and temsirolimus 15 mg weekly. Dose-limiting toxicities (DLTs) included mucositis, neutropenia, and thrombocytopenia. Other adverse events included grade 1/2 fatigue, anemia, and hyperglycemia. No objective responses were observed, but four patients experienced stable disease that lasted for at least 4 months. Compared with baseline, there was a significant increase in the serum levels of IGF-1 (p < 0.001) and IGFBP-3 (p = 0.019) on day 2. Compared with day 2, there were significant increases in the serum levels of IGF-1 (p < 0.001), IGF-2 (p = 0.001), and IGFBP-3 (p = 0.019) on day 8. A phase II study in women with metastatic breast cancer is ongoing.

Phase I study of temsirolimus in combination with EKB-569 in patients with advanced solid tumors.

Purpose Activation of EGFR can stimulate proliferative and survival signaling through mTOR. Preclinical data demonstrates synergistic activity of combined EGFR and mTOR inhibition. We undertook a phase I trial of temsirolimus (T, an mTOR inhibitor) and EKB-569 (E, an EGFR inhibitor) to determine the safety and tolerability. Methods The primary aim was to determine the maximally tolerated dose (MTD) of this combination in adults with solid tumors. Following the dose-escalation phase, (Cohort A), two subsequent cohorts were used to assess any pharmacokinetic (PK) interaction between the agents. Results Forty eight patients were enrolled. The MTD of this combination was E, 35 mg daily and T, 30 mg on days 1-3 and 15-17 using a 28-day cycle. The most common toxicities were nausea, diarrhea, fatigue, anorexia, stomatitis, rash, anemia, neutropenia, thrombocytopenia, and hypertriglyceridemia. Sixteen patients (36%) had at least one grade 3 toxicity. The most frequent grade 3/4 toxicities were diarrhea, dehydration, and nausea and vomiting (19% each). No grade 5 events were seen. Four patients had a partial response and 15 had stable disease. Clinical benefit was seen across a range of tumor types and in all cohorts. PK analysis revealed no significant interaction between E and T. Conclusions This combination of agents is associated with tolerable toxicities at doses that induced responses. PK studies revealed no interaction between the drugs. Further investigations of this targeting strategy may be attractive in renal cell carcinoma, non-small cell lung cancer, alveolar sarcoma, and carcinoid tumor.

A phase II study of gemcitabine in combination with tanespimycin in advanced epithelial ovarian and primary peritoneal carcinoma.

OBJECTIVE: To evaluate the efficacy and biological effects of the gemcitabine/tanespimycin combination in patients with advanced ovarian and peritoneal cancer. To assess the effect of tanespimycin on tumor cells, levels of the chaperone proteins HSP90 and HSP70 were examined in peripheral blood mononuclear cells (PBMC) and paired tumor biopsy lysates. METHODS: Two-cohort phase II clinical trial. Patients were grouped according to prior gemcitabine therapy. All participants received tanespimycin 154 mg/m(2) on days 1 and 9 of cycle 1 and days 2 and 9 of subsequent cycles. Patients also received gemcitabine 750 mg/m(2) on day 8 of the first treatment cycle and days 1 and 8 of subsequent cycles. RESULTS: The tanespimycin/gemcitabine combination induced a partial response in 1 gemcitabine naïve patient and no partial responses in gemcitabine resistant patients. Stable disease was seen in 6 patients (2 gemcitabine naïve and 4 gemcitabine resistant). The most common toxicities were hematologic (anemia and neutropenia) as well as nausea and vomiting. Immunoblotting demonstrated limited upregulation of HSP70 but little or no change in levels of most client proteins in PBMC and paired tumor samples. CONCLUSIONS: Although well tolerated, the tanespimycin/gemcitabine combination exhibited limited anticancer activity in patients with advanced epithelial ovarian and primary peritoneal carcinoma, perhaps because of failure to significantly downregulate the client proteins at clinically achievable exposures.

Phase I study of 17-allylamino-17 demethoxygeldanamycin, gemcitabine and/or cisplatin in patients with refractory solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD) and characterize the dose-limiting toxicities (DLT) of 17-AAG, gemcitabine and/or cisplatin. Levels of the proteins Hsp90, Hsp70 and ILK were measured in peripheral blood mononuclear cell (PMBC) lysates to assess the effects of 17-AAG. EXPERIMENTAL DESIGN: Phase I dose-escalating trial using a "3 + 3" design performed in patients with advanced solid tumors. Once the MTD of gemcitabine + 17-AAG + cisplatin was determined, dose escalation of 17-AAG with constant doses of gemcitabine and cisplatin was attempted. After significant hematologic toxicity occurred, the protocol was amended to evaluate three cohorts: gemcitabine and 17-AAG; 17-AAG and cisplatin; and gemcitabine, 17-AAG and cisplatin with modified dosing. RESULTS: The 39 patients enrolled were evaluable for toxicity and response. The MTD for cohort A was 154 mg/m(2) of 17-AAG, 750 mg/m(2) of gemcitabine, and 40 mg/m(2) of cisplatin. In cohort A, DLTs were observed at the higher dose level and included neutropenia, hyperbilirubinemia, dehydration, GGT elevation, hyponatremia, nausea, vomiting, and thrombocytopenia. The MTD for cohort C was 154 mg/m(2) of 17-AAG and 750 mg/m(2) of gemcitabine, with one DLT observed (alkaline phosphatase elevation) observed. In cohort C, DLTs of thrombocytopenia, fever and dyspnea were seen at the higher dose level. The remaining cohorts were closed to accrual due to toxicity. Six patients experienced partial responses. Mean Hsp90 levels were decreased and levels of Hsp70 were increased compared to baseline. CONCLUSIONS: 17-AAG in combination with gemcitabine and cisplatin demonstrated antitumor activity, but significant hematologic toxicities were encountered. 17-AAG combined with gemcitabine is tolerable and has demonstrated evidence of activity at the MTD. The recommended phase II dose is defined as 154 mg/m(2) of 17-AAG and 750 mg/m(2) of gemcitabine, and is currently being investigated in phase II studies in ovarian and pancreatic cancers. There is no recommended phase II dose for the cisplatin-containing combinations.

Phase II trial of lapatinib and topotecan (LapTop) in patients with platinum-refractory/resistant ovarian and primary peritoneal carcinoma.

OBJECTIVE: Resistance to chemotherapy is a major challenge in the treatment of ovarian/peritoneal cancer. One purported mechanism of topotecan resistance is the breast cancer resistance protein (BCRP) and P-glycoprotein (Pgp). We designed a phase II clinical trial evaluating the efficacy and adverse event profile of concomitant topotecan and lapatinib, a small molecule pan-erbB inhibitor that can block BCRP/Pgp efflux of topotecan. METHODS: Patients with platinum-refractory or resistant epithelial ovarian/peritoneal cancer were treated with topotecan 3.2 mg/m² IV on Day 1, 8 and 15 and lapatinib 1250 mg PO daily, continuously in 28 day cycles. The primary endpoint was response rate. For correlative studies, archived tissue was assessed for expression of EGFR, HER2, HIF-1α, CD31, and BCRP. RESULTS: Eighteen patients were enrolled and treated. Four experienced evidence of clinical benefit: one partial response and three with stable disease. Using a two-stage Simon design, the trial was stopped after the first stage due to insufficient activity. Grades 3+ and 4+ adverse events (AE) were experienced in 14 and 4 patients, respectively. The most common grade 3/4 AE were neutropenia (56%), thrombocytopenia (28%), and diarrhea (22%). CONCLUSIONS: The combination of lapatinib plus topotecan for the treatment of platinum refractory/resistant epithelial ovarian cancer lacks sufficient activity to warrant further investigation. In particular, hematologic adverse events were substantial. Expression of correlative study markers did not reveal patterns of predicted benefit or toxicity. Disruption of erbB signaling and BCRP/Pgp efflux with lapatinib was insufficient for overcoming topotecan resistance, suggesting alternative mechanisms of resistance are involved.

Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study.

BACKGROUND: Figitumumab is a fully human IgG2 monoclonal antibody targeting the insulin-like growth-factor-1 receptor (IGF-1R). Preclinical data suggest a dependence on insulin-like growth-factor signalling for sarcoma subtypes, including Ewing's sarcoma, and early reports show antitumour activity of IGF-1R-targeting drugs in these diseases. METHODS: Between January, 2006, and August, 2008, patients with refractory, advanced sarcomas received figitumumab (20 mg/kg) in two single-stage expansion cohorts within a solid-tumour phase 1 trial. The first cohort (n=15) included patients with multiple sarcoma subtypes, age 18 years or older, and the second cohort (n=14) consisted of patients with refractory Ewing's sarcoma, age 9 years or older. The primary endpoint was to assess the safety and tolerability of figitumumab. Secondary endpoints included pharmacokinetic profiling and preliminary antitumour activity (best response by Response Evaluation Criteria in Solid Tumours [RECIST]) in evaluable patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, number NCT00474760. FINDINGS: 29 patients, 16 of whom had Ewing's sarcoma, were enrolled and received a total of 177 cycles of treatment (median 2, mean 6.1, range 1-24). Grade 3 deep venous thrombosis, grade 3 back pain, and grade 3 vomiting were each noted once in individual patients; one patient had grade 3 increases in aspartate aminotransferase and gammaglutamyltransferase concentrations. This patient also had grade 4 increases in alanine aminotransferase concentrations. The only other grade 4 adverse event was raised concentrations of uric acid, noted in one patient. Pharmacokinetics were comparable between patients with sarcoma and those with other solid tumours. 28 patients were assessed for response; two patients, both with Ewing's sarcoma, had objective responses (one complete response and one partial response) and eight patients had disease stabilisation (six with Ewing's sarcoma, one with synovial sarcoma, and one with fibrosarcoma) lasting 4 months or longer. INTERPRETATION: Figitumumab is well tolerated and has antitumour activity in Ewing's sarcoma, warranting further investigation in this disease. FUNDING: Pfizer Global Research and Development.

Statistical analysis of comparative tumor growth repeated measures experiments in the ovarian cancer patient derived xenograft (PDX) setting.

Repeated measures studies are frequently performed in patient-derived xenograft (PDX) models to evaluate drug activity or compare effectiveness of cancer treatment regimens. Linear mixed effects regression models were used to perform statistical modeling of tumor growth data. Biologically plausible structures for the covariation between repeated tumor burden measurements are explained. Graphical, tabular, and information criteria tools useful for choosing the mean model functional form and covariation structure are demonstrated in a Case Study of five PDX models comparing cancer treatments. Power calculations were performed via simulation. Linear mixed effects regression models applied to the natural log scale were shown to describe the observed data well. A straight growth function fit well for two PDX models. Three PDX models required quadratic or cubic polynomial (time squared or cubed) terms to describe delayed tumor regression or initial tumor growth followed by regression. Spatial(power), spatial(power) + RE, and RE covariance structures were found to be reasonable. Statistical power is shown as a function of sample size for different levels of variation. Linear mixed effects regression models provide a unified and flexible framework for analysis of PDX repeated measures data, use all available data, and allow estimation of tumor doubling time.

Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.

I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY's prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.

Characterization of a RAD51C-silenced high-grade serous ovarian cancer model during development of PARP inhibitor resistance.

Acquired PARP inhibitor (PARPi) resistance in BRCA1- or BRCA2-mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived ovarian cancer xenograft PH039, which lacks HR gene mutations but harbors RAD51C promoter methylation, was selected for PARPi resistance by cyclical niraparib treatment in vivo. PH039 acquired PARPi resistance by the third treatment cycle and grew through subsequent treatment with either niraparib or rucaparib. Transcriptional profiling throughout the course of resistance development showed widespread pathway level changes along with a marked increase in RAD51C mRNA, which reflected loss of RAD51C promoter methylation. Analysis of ovarian cancer samples from the ARIEL2 Part 1 clinical trial of rucaparib monotherapy likewise indicated an association between loss of RAD51C methylation prior to on-study biopsy and limited response. Interestingly, the PARPi resistant PH039 model remained platinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure can reverse RAD51C methylation and restore RAD51C expression, but also provide a model for studying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.

Phase I and Pharmacokinetic Study of Romidepsin in Patients with Cancer and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study.

PURPOSE: Romidepsin dosing recommendations for patients with malignancy and varying degrees of hepatic dysfunction was lacking at the time of regulatory approval for T-cell lymphoma. We conducted a multicenter phase I clinical trial (ETCTN-9008) via the NCI Organ Dysfunction Working Group to investigate safety, first cycle MTD, and pharmacokinetic profile of romidepsin in this setting. PATIENTS AND METHODS: Patients with select advanced solid tumors or hematologic malignancies were stratified according to hepatic function. Romidepsin was administered intravenously on days 1, 8, and 15 of a 28-day cycle and escalation followed a 3 + 3 design in moderate and severe impairment cohorts. Blood samples for detailed pharmacokinetic analyses were collected after the first dose. RESULTS: Thirty-one patients received one dose of romidepsin and were evaluable for pharmacokinetic analyses in normal (n = 12), mild (n = 8), moderate (n = 5), and severe (n = 6) cohorts. Adverse events across cohorts were similar, and dose-limiting toxicity occurred in two patients (mild and severe impairment cohorts). The MTD was not determined because the geometric mean AUC values of romidepsin in moderate (7 mg/m2) and severe (5 mg/m2) impairment cohort were 114% and 116% of the normal cohort (14 mg/m2). CONCLUSIONS: Data from the ETCTN-9008 trial led to changes in the romidepsin labeling to reflect starting dose adjustment for patients with cancer and moderate and severe hepatic impairment, with no adjustment for mild hepatic impairment.

Anti-CDCP1 immuno-conjugates for detection and inhibition of ovarian cancer.

CUB-domain containing protein 1 (CDCP1) is a cancer associated cell surface protein that amplifies pro-tumorigenic signalling by other receptors including EGFR and HER2. Its potential as a cancer target is supported by studies showing that anti-CDCP1 antibodies inhibit cell migration and survival in vitro, and tumor growth and metastasis in vivo. Here we characterize two anti-CDCP1 antibodies, focusing on immuno-conjugates of one of these as a tool to detect and inhibit ovarian cancer. Methods: A panel of ovarian cancer cell lines was examined for cell surface expression of CDCP1 and loss of expression induced by anti-CDCP1 antibodies 10D7 and 41-2 using flow cytometry and Western blot analysis. Surface plasmon resonance analysis and examination of truncation mutants was used to analyse the binding properties of the antibodies for CDCP1. Live-cell spinning-disk confocal microscopy of GFP-tagged CDCP1 was used to track internalization and intracellular trafficking of CDCP1/antibody complexes. In vivo, zirconium 89-labelled 10D7 was detected by positron-emission tomography imaging, of an ovarian cancer patient-derived xenograft grown intraperitoneally in mice. The efficacy of cytotoxin-conjugated 10D7 was examined against ovarian cancer cells in vitro and in vivo. Results: Our data indicate that each antibody binds with high affinity to the extracellular domain of CDCP1 causing rapid internalization of the receptor/antibody complex and degradation of CDCP1 via processes mediated by the kinase Src. Highlighting the potential clinical utility of CDCP1, positron-emission tomography imaging, using zirconium 89-labelled 10D7, was able to detect subcutaneous and intraperitoneal xenograft ovarian cancers in mice, including small (diameter <3 mm) tumor deposits of an ovarian cancer patient-derived xenograft grown intraperitoneally in mice. Furthermore, cytotoxin-conjugated 10D7 was effective at inhibiting growth of CDCP1-expressing ovarian cancer cells in vitro and in vivo. Conclusions: These data demonstrate that CDCP1 internalizing antibodies have potential for killing and detection of CDCP1 expressing ovarian cancer cells.