Abstract
PURPOSE: A phase I trial of intravesical bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab was conducted in patients with high grade non-muscle invasive bladder ...cancer who had persistent or recurrent disease after failing treatment with at least 2 courses of intravesical therapy (one of which had to contain BCG) or BCG followed by maintenance BCG. The primary objective was to determine the safety of this combination. Secondary end points included response to treatment at 19 weeks (end of treatment) and 3 months post treatment.
MATERIALS AND METHODS: A total of 9 patients with recurrent/persistent high-grade non-muscle invasive bladder cancer after at least two courses of intravesical therapy or one course of BCG treatment followed by one course of maintenance BCG were enrolled in the study. Six doses of pembrolizumab were given every 3 weeks over 16 weeks given concurrently with 6 weekly doses of BCG beginning at week 7. Patient safety was evaluated during and for 30 days following pembrolizumab treatment. Preliminary combination efficacy was determined at 19 weeks using cystoscopy. Bladder biopsy was performed in patients with suspicious lesions.
RESULTS: The combination of BCG and pembrolizumab was well tolerated at both 100mg and 200mg fixed doses. Fatigue and cystitis-type symptoms (burning, spasm, urgency, sensitivity, and frequency) were the most common adverse events and all cases were either grade 1 or 2. Two patients died during the trial period. One patient died due to progression of low grade upper urinary tract transitional cell carcinoma. The other patient died after cystectomy (for progressive disease) due to causes unrelated to the trial treatment. Of the 9 patients treated, 6 (78%) had no evidence of disease in the bladder and 1 had a mixed response (progression in the upper urinary tract only) at 19 weeks (end of treatment) while 5 (56%) remained disease-free at the 3 month follow up.
CONCLUSIONS: The combination of BCG and pembrolizumab was well tolerated with subjects exhibiting the expected adverse effects associated with the use of both medications. Intravesical BCG and pembrolizumab may have clinical activity in non-muscle invasive bladder cancer recurring after repeated intravesical therapy. .A phase III trial is now open and enrolling in the United States and other countries (NCT03711032).
Citation Format: Shaheen Alanee, Ahmed El Zawahry, Sherjeel Sana, Kevin McVary, Kathy Robinson, Krishna A. Rao. Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous Pembrolizumab in high grade nonmuscle invasive bladder cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT047.
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e23043
Background: Cardiotoxicity is a known side effect of anthracyclines & trastuzumab. Dilated cardiomyopathy is the most common form of cardiotoxicity associated with this ...treatment. Cardiovascular disease & cancer are common conditions in the geriatric populations. These comorbidities complicate the treatment of geriatric breast cancer patients. The purpose of this study was to determine the cardiotoxic effects of chemotherapy & trastuzumab in a geriatric population of breast cancer patients. Methods: An institutional database of a total of 269 patients with histologically confirmed invasive or in-situ breast cancer with age 65 years or older at the time of diagnosis was reviewed in an IRB approved fashion. Patients were divided in groups depending on the therapy (AC/TAC, CMF, TC and Trastuzumab) they received. Fisher’s exact test was used to calculate overall survival (OS). Results: Of the 269 patients, 72 (26.8%) were offered chemotherapy & 197 (73.2%) were not. Of the patients offered chemotherapy, 58 (21.6%) accepted treatment & 14 (5.2%) declined. 17 (6.7%) had an early termination, AC n = 11,( 4.1%), TAC n = 13, (4.8%), CMF n = 0, (0%), Trastuzumab n = 12, (4.5%), TC n = 11, (4.1%). Cardiovascular risk factors taken into consideration were, CAD n = 30, (13.8%), HLD n = 23, (10.6%), HTN n = 98, (45.2%), HTN/HLD n = 66, (30.4%), DM (N = 45, (16.7%), Smoking n = 121, (46.4%) & BMI > 30, n = 116,( 48.1%). Patients completing chemotherapy had higher OS than patients who had early termination (P = 0.017). Of the 24 patients who received Anthracycline containing regimen, 1 experienced cardiotoxicity. There was no statistically significant difference in OS between AC, TAC & Trastuzumab (P = 0.570, P = 0.547, P = 0.614). A decrease in OS was seen for patient who received TC (P = 0.002). Of the 12 who received trastuzumab, 1 experienced cardiotoxicity. There was a significant association between patients with a high BMI ( > 30) & increased cardiovascular comorbidities (P = 0.0009) but had no impact early on termination of chemotherapy or OS, NS (P = 0.7). Conclusions: The cardiotoxic effect of anthracyclines and trastuzumab are well known, however in our study, only 2 elderly breast cancer patients who received chemotherapy experienced cardiotoxicity. As would be expected, those who completed chemotherapy had improved OS. There were no difference in OS between AC, TAC and Trastuzumab, however TC treatment was associated with a decrease in OS.BMI had an impact on cardiovascular comorbidities but not on early termination of chemotherapy or OS.
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e12053
Background: The NCI SEER data demonstrated that age adjusted incidence rate of geriatric breast cancer is 427.5 per 100,000. Mortality rates for breast cancer have improved over ...the last 20 years,but the risk of breast cancer death has decreased 3 fold more rapidly in younger vs. geriatric population. Comorbid illnesses are more prevalent in elderly & therapy offered is often less aggressive. The objective of this study was examine practice patterns in a rural geriatric breast cancer population. The patients were divided into groups with life expectancies (LE) > 10 years or not. Analysis was also performed in groups based on age ranges. Methods: An institutional database of 269 patients with histologically confirmed invasive or in-situ breast cancer with age 65 or older at the time of diagnosis was reviewed in an IRB approved fashion. Data was collected on age at diagnosis, LE, and the rates of chemotherapy, surgery, radiation therapy, multidisciplinary discussion, clinical trials, Adjuvant Online!, & endocrine therapy offered. LE data was divided into patients with greater than 10 years of life expectancy or not at the time of diagnosis. A separate analysis examined the rates of the above in age ranges of 65-70, 71-80, and 81 plus. Variations in significance were identified using Fishers Exact Test. Results: 44 patients (16.4%) had a LE at diagnosis of < 10 years. Surgery was offered in n=262 patients (97.4%). Radiation therapy was offered in n=170 patients (64.9%). Endocrine therapy was offered in n= 221 patients (83.1%). Chemotherapy was offered in n= 72 patients (27.2%). In the greater than or less than 10 year LE group, statistically significant variations were noted in the rates of radiation (p=0.0047) & chemotherapy (p=0.0067) treatments offered to patients based on their life expectancy. When patients were grouped by age range, statistically significant variations were noted in the rates of radiation treatment (p=0.0221), endocrine treatment (p=0.032), chemotherapy (p≤0.0001), & participation in clinical trials (p=0.0218). Conclusions: Our study identified statistically significant differences in the rates of radiation & chemotherapy offered to patients based on their life expectancy. Statistically significant differences in rates of radiation, endocrine therapy, chemotherapy, and participation in clinical trials were observed based on the age ranges of patients. No differences were noted in the rates of surgery offered, use of Adjuvant Online, and multidisciplinary discussion based on LE & age range.
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e12048
Background: Aromatase inhibitors (AIs) are commonly used in treatment of ER & PR + breast cancer in postmenopausal women. It is well known that AIs can lead to bone loss. ...Bisphosphonates have been used to counteract bone loss due to AI use. The objective of this study was to evaluate the use of bisphosphonates in elderly females above 65 years, with ER + breast cancer on AIs, in a rural setting, and to examine the effects of oral vs. IV bisphosphonates on overall survival (OS) in geriatric patients. We also examined the effects of alcohol use on bone health in this population. Methods: An institutional database of 269 patients with histologically confirmed invasive or in-situ breast cancer with age 65 or older at the time of diagnosis was reviewed in an IRB approved fashion. 176 patients were ER+ and had DEXA diagnosed osteoporosis or osteopenia.They were treated with anastrozole n = 88 (50)% or letrozole n = 88 (50%). Type of bisphosphonate treatments used ,impact of alcohol consumption & data on OS were collected from the database. Results: 176 patients (65.4%) were ER+ and had DEXA diagnosed osteoporosis or osteopenia. Alendronate was used in 15 patients (8.5%), ibandronate was used in 3 patients (1.7%), risedronate was used in 1 patient (0.6%), and zoledronate was used in 44 patients (25%). IV bisphosphonates were used in 44 patients (69.8%) and oral were used in 19 patients (30.2%). Majority of patietns were on calcium + D supplementation.10% of non-alcohol users had osteopenia/osteoporosis compared to 15% of former alcohol users and 29% of current alcohol users. LogRank testing found no significant difference between survival based on bisphosphonate use . Similar statistical analysis found no significant difference between survival based between IV and oral bisphosphonates. Conclusions: Our study showed that geriatric patients with ER + breast cancer on AI therapy were adequately managed for osteopenia and osteoporosis with the use of bisphosphonates (oral and IV) in a rural setting. There was no significant effect on overall survival (OS) , with use of bisphosphonates during AI therapy. No significant difference in OS was identified for patients taking IV vs. oral bisphosphonates,but this was attributed to very small number of patients that experienced death as an event in this population. Bisphosphonates were also well tolerated, with only 1 patient noting ONJ and one patient with renal toxicity. Current and former alcohol use was found to be correlated with increased rates of osteopenia/osteoporosis in this population.
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e12052
Background: Compliance is a serious issue for breast cancer patients on endocrine therapy. There are various factors that may alter compliance across different age groups e.g. ...side effects, cognitive impairment, socioeconomic status etc. Noncompliance to therapy leads to early discontinuation and poor longterm outcome. The purpose of this study was to examine compliance rates with endocrine therapy i.e. aromatase inhibitors & tamoxifen in different age groups of geriatric breast cancer patients and determine its tolerability and impact on survival. Methods: An institutional database of a total of 269 patients with histologically confirmed invasive or in-situ breast cancer with age 65 years or older at the time of diagnosis was reviewed in an IRB approved fashion. Adjuvant endocrine therapy included tamoxifen, letrozole, anstrozole and fulvestrant. Patients were further subdivided into age groups. Compliance was measured as an early termination of therapy. Fisher’s exact test was used to calculate statistical difference. Results: Out of 266 eligible patients, 221 (83.1%) were offered endocrine therapy. 216 (81.2%) accepted endocrine therapy and 5 (1.9%) declined treatment. Distribution of each therapy was as follows:Anastrozole n = 90, (33.5%), Letrozole n = 88, (32.7%), Fulvestrant n = 6,( 2.3%), Tamoxifen n = 64, (23.8%). Early termination n = 44, (21.4%). Between the ages 65-70, n = 17,(18.had an early termination or noncompliance to therapy, in the age group from 71-80 age group,n = 24,(26.4%) had an early termination, and ages 81 and above,n = 3 (12.5%) had an early termination. There were no statistical differences between Anastrozole, Letrozole, Tamoxifen & Fulvestrant (P = 0.8275, P = 0.4589, P = 0.6136). There was also no statistical difference between age groups (P = 0.2742). Overall survival was worse with early termination,n = 20 vs not n = 6 but did not reach statistical significance ( P = 0.7). Conclusions: In breast cancer patients 65 and older, age can be a factor in noncompliance. However, in our study there were no correlation between age groups and compliance or with which drug used. Tolerability was similar between each endocrine therapy, across different age groups in this geriatric breast cancer population, in a rural setting.
Alterations in nuclear pore complex (NPC) genes have been previously associated with response to chemotherapy. Using agnostic exome sequencing, we envisioned that new alleles in NPC genes, predictive ...of sensitivity to platinum treatment, could be discovered.
Twenty-two platinum-sensitive and six platinum-resistant ovarian cancer patients were tested. Platinum sensitivity was defined as disease-free survival greater than 6 months. Next-generation sequencing of exomes was used to compare platinum-sensitive and platinum-resistant patients. Single nucleotide variants (SNVs) associated with platinum sensitivity in NPC genes (n=30 genes) were identified.
SNVs in three NPC genes were associated with response to platinum on univariate analysis. SNV rs79419059 (10T>C) in Nucleoporin 107 (Nup107) was associated with platinum resistance (P=0.0061), whereas rs2302811 (3662-4A>G) in Nucleoporin 188 (Nup188) and rs77246077 (3420-67T>A) in Nucleoporin 214 (Nup214) were associated with platinum sensitivity (P=0.0483 and 0.0091, respectively). Controlling for other confounders, multivariate age-adjusted Cox proportional hazard analysis showed rs79419059 to be significantly associated with platinum resistance (odds ratio: 4.519, 95% confidence interval: 1.317-15.501, P=0.0457).
We identified a variant in the 3'-UTR region Nup107 unique to sensitivity to platinum in ovarian cancer. With validation of this variant, it is possible that a new marker predictive of patient response may be identified.
Abstract
BACKGROUND
Ruxolitinib is a novel, potent, selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3. Ruxolitinib ...interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression.
METHODS
Newly diagnosed patients with MGMT not hypermethylated, Glioblastoma or grade III glioma were recruited to Arm 1. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3 + 3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily. Patients with MGMT hypermethylated glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks.
RESULTS
45 patients had survival data, 25 patients were in Arm I and 20 arm in II. The median OS and PFS were 18.2 (95% CI: 3.6-NA) months for Arm 1 and were not reached for Arm 2. OS and PFS Rate at 1 year was 61% (95% CI: 43-85%) and 51% (35-76%) for Arm 1, and 95% (85-100%) for Arm 2 (p=0.01 and p= 0.002), respectively. 9 patients had partial response, 16 patients were stable, and 28 patients had progression.
CONCLUSION
Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone..
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