[Show abstract][Hide abstract] ABSTRACT: Demethylation process is necessary for the expression of various factors involved in chemotherapy cytotoxicity or resistance. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1. We hypothesized that azacitidine and oxaliplatin combination therapy may restore platinum sensitivity. We treated patients with cancer relapsed/refractory to any platinum compounds (3 + 3 study design) with azacitidine (20 to 50 mg/m(2)/day intravenously (IV) over 15 to 30 min, D1 to 5) and oxaliplatin (15 to 30 mg/m(2)/day, IV over 2 h, D2 to 5) (maximum, six cycles). Platinum content, LINE1 methylation (surrogate of global DNA methylation), and CTR1 expression changes (pre- vs. post-treatment) were assessed. Drug pharmacokinetics were analyzed.
Thirty-seven patients were treated. No dose-limiting toxicity (DLT) was noted at the maximum dose. The most common adverse events were anemia and fatigue. Two (5.4%) patients had stable disease and completed six cycles of therapy. Oxaliplatin (D2) and azacitidine (D1 and 5) mean systemic exposure based on plasma AUCall showed dose-dependent interaction whereby increasing the dose of oxaliplatin reduced the mean azacitidine exposure and vice versa; however, no significant differences in other non-compartmental modeled parameters were observed. Blood samples showed universal reduction in global DNA methylation. In tumor samples, hypomethylation was only observed in four out of seven patients. No correlation between blood and tumor demethylation was seen. The mean cytoplasmic CTR1 score decreased. The pre-dose tumor oxaliplatin levels ranged from <0.25 to 5.8 μg/g tumor. The platinum concentration increased 3- to 18-fold. No correlation was found between CTR1 score and oxaliplatin level, which was found to have a trend toward correlation with progression-free survival.
Oxaliplatin and azacitidine combination therapy was safe. CTR1 expression was not correlated with methylation status or tissue platinum concentration.
[Show abstract][Hide abstract] ABSTRACT: Background: Antiviral therapy (AVT) improves hepatic outcomes in hepatitis C virus (HCV) infected cancer patients (pts), but such pts are frequently excluded from clinical trials on AVT or chemotherapy (CHE). We aimed to describe the safety and clinically significant drug-drug interactions (DDIs) observed in cancer pts who received CHE and AVT simultaneously.
Methods: Medical records of HCV-infected cancer pts who received CHE + AVT at MD Anderson between 1/2008- 4/2015 (1/2008-10/2012 retrospectively; 11/2012-4/2015 prospectively) were evaluated. Pts received CHE + AVT if based on metabolism and clearance, a DDI was unlikely. Adverse events (AEs) were graded according to the Division of AIDS table, v1.0. Grade 3/4 AEs were considered serious (SAEs).
Results: Nineteen pts who received CHE and AVT were studied (13 prospectively). AVT was initiated in pts undergoing CHE to normalize liver function tests and reduce liver disease progression (80%) or improve oncologic outcome of pts with non-Hodgkin lymphoma (5%). CHE was started in pts receiving AVT because of cancer progression (15%). Most pts were female (74%), white (58%), non-cirrhotic (89%), had solid tumors (58%), and genotype 1 (63%). AVTs used were pegylated interferon (IFN) based regimens [IFN + ribavirin (RBV) (37%); sofosbuvir (SOF) + IFN + RBV (16%)], or IFN-free regimens [SOF + RBV (16%); SOF + simeprevir (SIM) (11%); SOF + ledipasvir (LDV) (21%)]. Pts received CHE + AVT for a median of 85 days (IQR, 54-166 days). CHE used were corticosteroids (n=7), tamoxifen (n=5), trastuzumab (n=3), tacrolimus (n=2), bortezomib, cyclophosphamide, docetaxel, 5-flurouracil, gemcitabine, hydroxyurea, lenalidomide, letrozole, oxaliplatin, pertuzumab, and rituximab (n=1 each). CHE given with IFN-based AVT was more commonly associated with grade 1-4 AEs (Hematological 100% vs 44%; psychiatric 70% vs 30%) and SAEs (70% vs 44%) when compared with IFN-free AVT. SAEs (grade 3 neutropenia and thrombocytopenia) observed in IFN-free AVT were attributed to CHE (gemcitabine, rituximab) or RBV but not to SOF, SIM or LDV. The occurrence of AEs led to AVT dose modification in 7 pts (IFN, 4; RBV, 7) and discontinuation in 3 pts (all on IFN+RBV). CHE dose was modified in 2 pts without requiring discontinuation. Sustained virological response rates were higher with SOF-based than IFN-based AVT (overall 86% vs 57%).
Conclusion: IFN-sparing regimes seem to be safe when administered concomitantly with selected CHE. Pts on such combination should be closely monitored.
The Liver Meeting® 2015, San Francisco, CA; 11/2015
[Show abstract][Hide abstract] ABSTRACT: Radiation therapy controls local disease but also prompts the release of tumor-associated antigens and stress-related danger signals that primes T cells to promote tumor regression at unirradiated sites known as the abscopal effect. This may be enhanced by blocking inhibitory immune signals that modulate immune activity through a variety of mechanisms. Indeed, abscopal responses have occurred in patients with lung cancer or melanoma when given anti-CTLA4 antibody and radiation. Other approaches involve expanding and reinfusing T or NK cells or engineered T cells to express receptors that target specific tumor peptides. These approaches may be useful for immunocompromised patients receiving radiation. Preclinical and clinical studies are testing both immune checkpoint-based strategies and adoptive immunotherapies with radiation.
[Show abstract][Hide abstract] ABSTRACT: Fast and accurate diagnostic systems are needed for further implementation of precision therapy of BRAF-mutant and other cancers. The novel IdyllaTMBRAF Mutation Test has high sensitivity and shorter turnaround times compared to other methods. We used Idylla to detect BRAF V600 mutations in archived formalin-fixed paraffin-embedded (FFPE) tumor samples and compared these results with those obtained using the cobas 4800 BRAF V600 Mutation Test or MiSeq deep sequencing system and with those obtained by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory employing polymerase chain reaction-based sequencing, mass spectrometric detection, or next-generation sequencing. In one set of 60 FFPE tumor samples (15 with BRAF mutations per Idylla), the Idylla and cobas results had an agreement of 97%. Idylla detected BRAF V600 mutations in two additional samples. The Idylla and MiSeq results had 100% concordance. In a separate set of 100 FFPE tumor samples (64 with BRAF mutation per Idylla), the Idylla and CLIA-certified laboratory results demonstrated an agreement of 96% even though the tests were not performed simultaneously and different FFPE blocks had to be used for 9 cases. The IdyllaTMBRAF Mutation Test produced results quickly (sample to results time was about 90 minutes with about 2 minutes of hands on time) and the closed nature of the cartridge eliminates the risk of PCR contamination. In conclusion, our observations demonstrate that the Idylla test is rapid and has high concordance with other routinely used but more complex BRAF mutation-detecting tests.
[Show abstract][Hide abstract] ABSTRACT: Preclinically, pazopanib/lapatinib combination acted synergistically to suppress the activity of multiple tyrosine kinases, including VEGFR-1, 2, 3, PDGFR and c-kit (pazopanib), HER1/EGFR and HER2 (lapatinib), and several other tyrosine kinases including c-Met through, plausibly, network inhibition effects. Clinically, continuous dosing of pazopanib/lapatinib combination was associated with a higher response rate than with lapatinib monotherapy, with poor tolerance. We explored multiple intermittent dose levels of pazopanib combined with continuous daily dosing of lapatinib in patients with solid tumors.
The present study used a phase 1, modified 3 + 3, dose-escalation design to evaluate the safety and tolerability of the combination of orally received pazopanib once every other day with continuous daily dosing of lapatinib for 28 days. In the expansion phase, tumor response was evaluated in patients with specific genetic alterations (HER2 amplification, HER2 mutation, c-Met amplification, c-Met mutation, and EGFR mutation).
Twenty-four patients were treated. The most common drug-related adverse events were fatigue 7/24 (29 %), skin rash 5/21 (21 %), and diarrhea 3/24 (17 %), with 4/24 (16 %) patients experiencing grade ≥3 drug-related adverse events. Escalation to the FDA-approved dose (800 mg daily for pazopanib and 1500 mg every day for lapatinib) was not feasible due to toxicities. Pazopanib 200 mg every other day + lapatinib 500 mg daily was considered the maximum tolerated dose (MTD). No tumor response was observed, including in patients with the specific molecular genetic alterations tested.
Every other day dosing of pazopanib combined with daily lapatinib was tolerated at the established MTD, but no complete or partial tumor responses were observed at these dose levels.
Cancer Chemotherapy and Pharmacology 07/2015; 76(3). DOI:10.1007/s00280-015-2824-6 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with advanced hepatocellular carcinoma (HCC) have limited effective therapeutic options. Given the rapid advanced in drug development and emergence of novel agents, we analyzed the characteristics and outcomes of HCC patients treated on early phase trials with an emphasis on targeted therapies.
We reviewed the records of consecutive HCC patients evaluated in the Phase I Clinical Trials Program at MD Anderson from March 2004.
Thirty-nine patients were not treated due to poor performance status (n = 22, 56%) and decision to pursue alternate therapies (n = 10, 27%). Of 61 treated patients (median age, 60 years; median prior therapies, 3), eight patients (13%) attained stable disease lasting ≥6 months; four (7%) had a partial response, mainly with anti-angiogenic or multikinase inhibitors. Median Phase I progression-free survival (PFS) was 2.6 months versus 4.4 months (p 0.019) and 4.1 months (p 0.27) for their first-, and second-line FDA-approved therapy. Molecular analysis showed frequent PTEN loss (10/19 patients, 53%) and P53 mutation (4/4 patients tested). On multivariate analysis, independent factors predicting shorter survival were white ethnicity/race (p 0.031), cirrhosis (p 0.016), and serum sodium (p 0.0013).
In our heavily-pretreated HCC patients, the phase I PFS was comparable to that of 2nd-line therapy, highlighting a potential role for clinical trials after progression on first-line therapy. The response rate (SD>6 months/PR) of 20% was observed with early signals of activity in regimens combining inhibitors of angiogenesis, multiple kinases and mTOR with preliminary molecular analysis revealing prevalence of PTEN loss.
[Show abstract][Hide abstract] ABSTRACT: We determined the frequency of recurrent hotspot mutations in 46 cancer-related genes across tumor histologies in patients with advanced cancer.
We reviewed data from 500 consecutive patients who underwent genomic profiling on an IRB-approved prospective clinical protocol in the Phase I program at the MD Anderson Cancer Center. Archival tumor DNA was tested for 740 hotspot mutations in 46 genes (Ampli-Seq Cancer Panel; Life Technologies, CA).
Of the 500 patients, 362 had at least one reported mutation/variant. The most common likely somatic mutations were within TP53 (36%), KRAS (11%), and PIK3CA (9%) genes. Sarcoma (20%) and kidney (30%) had the lowest proportion of likely somatic mutations detected, while pancreas (100%), colorectal (89%), melanoma (86%), and endometrial (75%) had the highest. There was high concordance in 62 patients with paired primary tumors and metastases analyzed. 151 (30%) patients had alterations in potentially actionable genes. 37 tumor types were enrolled; both rare actionable mutations in common tumor types and actionable mutations in rare tumor types were identified.
Multiplex testing in the CLIA environment facilitates genomic characterization across multiple tumor lineages and identification of novel opportunities for genotype-driven trials.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Combining agents that block both the VEGF and PI3K/AKT/mTOR pathways may be synergistic. We explored a novel dosing schedule to assess safety, toxicity and activity in patients with advanced solid tumors.
Patients and methods:
Patients with refractory solid tumors were enrolled in a modified 3 + 3 Phase I dose escalation study to determine dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a combination of everolimus (mTOR inhibitor) and pazopanib (tyrosine kinase inhibitor with anti-VEGF activity). An expansion cohort selected for patients with molecular alterations in the PI3K/AKT/mTOR pathway.
Sixty-two patients were enrolled; median age was 60 years; 29 were women. The MTD was pazopanib 600 mg every other day (QOD) alternating with everolimus 10 mg PO QOD. DLTs were grade 3 thrombocytopenia and creatinine elevation. Most common toxicities of any grade were thrombocytopenia, transaminitis, leukopenia/neutropenia and lipid abnormalities. Among 52 patients evaluable for response, the clinical benefit rate (CBR) was 27 % (14/52) including four partial responses (PR), and 10 stable disease (SD) ≥6 months. 26 of 45 patients evaluated for molecular alterations had at least one alteration in the PI3K/AKT/mTOR pathway. CBR in patients with a matched alteration was 27 % (7/26) versus 26 % (5/19) for patients without an alteration (p = 0.764). However, 64% of those with CBR and molecular testing done for alteration in the PI3K/AKT/mTOR pathway were positive.
Combination treatment with pazopanib and everolimus was well tolerated and demonstrated activity in solid tumors. Further exploration of this combination and molecular correlation with treatment outcomes is warranted.
Investigational New Drugs 04/2015; 33(3). DOI:10.1007/s10637-015-0238-2 · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Advanced non-small cell lung cancer (NSCLC) patients were treated as part of a Phase I dose escalation and expansion study evaluating a true human monoclonal antibody targeting IL-1α (Xilonix), which is intended to modulate the malignant phenotype-inhibiting tumor growth, spread and offering relief of symptoms.
Sixteen NSCLC patients were included. Patients failed a median of 4 chemotherapy regimens, including 10/16 failing anti-EGFR therapy. Disease progression was evaluated using a multi-modal approach: tumor response, patient reported outcomes (EORTC-QLQC30), and lean body mass (LBM). Patients received infusions every 2 or 3 weeks until progression, and were followed 24 months to assess survival.
There were no infusion reactions, dose-limiting toxicities, or deaths due to therapy. Albeit not statistically significant, there was a trend in IL-6 (-2.6 ± 18.5 (0.1 [-2.8-2.4]), platelet counts (-11 ± 54 (-4[-36.0-1.0]), CRP (-3.3 ± 30.2 (0.4 [-10.7-1.8]) and LBM (1.0 ± 2.5 (0.4 [-0.5-2.6]). Self-reported outcomes revealed reductions in pain, fatigue and improvement in appetite. Median survival was 7.6 (IQR 4.4-11.5) months, stratification based on prior anti-EGFR therapy revealed a median survival of 9.4 months (IQR 7.6-12.5) for those pretreated (N = 10) versus a survival of 4.8 months (IQR 4.3-5.7) for those without (N = 6, logrank p = 0.187).
Xilonix was well tolerated, with gains in LBM and improvement in symptoms suggesting a clinically important response. Although not statistically significant, the survival outcomes observed for patients with and without prior anti-EGFR therapy raises intriguing questions about the potential synergy of IL-1α blockade and anti-EGFR therapy. Further study for this agent in NSCLC is warranted.
Investigational New Drugs 03/2015; 33(3). DOI:10.1007/s10637-015-0226-6 · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Olanzapine is used for treatment of psychiatric conditions but causes substantial weight gain. This study assessed safety, efficacy, and changes in metabolic cytokines associated with olanzapine administration in patients with cachexia due to advanced cancer.
Patients with cancer-related cachexia were treated with olanzapine (doses ranging from 2.5 to 20 mg daily by mouth). Patients also received anti-neoplastic treatments. Serum samples were collected at baseline and after weeks 1, 2, 4, and 8 for analysis of levels of leptin, growth hormone, ghrelin, and interleukin-6 (IL-6).
Of the 39 participants, 31 were evaluable for weight change (N = 6 excluded for new ascites; N = 2, incomplete body weight of data). Toxicities related to olanzapine were somnolence (n = 1), pancreatitis (n = 1), extrapyramidal symptoms (n = 1), and nausea/vomiting (n = 1) (all grade 2). The recommended dose of Olanzapine is 20 mg PO daily for cancer patients (same as FDA approved dose for psychiatric conditions). Samples from 29 patients were eligible for analysis of serum cytokine levels. Mean values of leptin, ghrelin, and growth hormone did not change on treatment, though IL-6 levels increased, perhaps due to tumor progression. There was no association between changes in cytokines and weight. The mean change in slope of weight loss before versus after therapy was 0.24 (95 % CI, -0.08, 0.56; p = 0.13) indicating a trend, albeit not reaching statistical significance, toward attenuation of weight loss.
Changes in metabolic cytokines and body weight did not correlate. Treatment with olanzapine had only a modest effect in altering the trajectory of weight loss.
Supportive Care Cancer 02/2015; 23(9). DOI:10.1007/s00520-015-2625-9 · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objectives of this study were to evaluate the tolerability and efficacy of valproic acid (VPA) and lenalidomide.
In this 3+3 design study, VPA was administered daily on a 7-day-on, 7-day-off schedule, and lenalidomide was administered daily for 28 days. Because of the response noted during the dose-escalation phase, 12 additional patients with adenoid cystic carcinoma (ACC) received the maximum tolerated dose (MTD) in a dose-expansion phase.
Twenty-six patients with advanced cancer (14 men/12 women), median age of 56 years (range 38-70 years), and a median number of two prior therapies (range 0-12) were enrolled. The most common toxicities were fatigue, rash, neutropenia, thrombocytopenia, and change in mental status. Dose-limiting toxic (DLT) effects were grade III confusion (n = 3), somnolence (n = 1), and gait disturbance (n = 1). The MTD was reached at VPA 30 mg/kg and lenalidomide 25 mg. Although only two of the 12 patients from the dose-expansion phase had DLT during the first cycle at the MTD, during subsequent cycles the majority of patients required dose reduction of VPA to 5-20 mg/kg because of fatigue and drowsiness. No significant tumor reductions were noticed in patients with ACC, but seven of these patients had stable disease over four cycles. Of non-ACC patients, one patient with melanoma and one patient with parathyroid carcinoma had stable disease for six cycles and eight cycles, respectively.
Lenalidomide combined with VPA was well tolerated. We recommend starting VPA at 5 mg/kg and titrating upward to 20 mg/kg. No significant tumor reductions were noticed in patients with ACC.
Cancer Chemotherapy and Pharmacology 02/2015; 75(4). DOI:10.1007/s00280-015-2695-x · 2.77 Impact Factor