A phase II trial to evaluate pemetrexed clinical responses in relation to tumor methylthioadenosine phosphorylase (MTAP) gene status in patients with previously treated metastatic urothelial carcinoma.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 385-385 ◽  
Author(s):  
Omar Alhalabi ◽  
Matthew T Campbell ◽  
Rebecca Slack-Tidwell ◽  
Arlene O. Siefker-Radtke ◽  
Amishi Yogesh Shah ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Response Rate ◽  
Synthetic Lethality ◽  
Objective Response ◽  
The Cancer Genome Atlas ◽  
Dynamic Monitoring ◽  
Nucleotide Synthesis ◽  
Metastatic Urothelial Carcinoma

385 Background: According to The Cancer Genome Atlas, 26.8% of bladder tumors harbor homozygous deletion of the MTAP gene, which encodes for an essential enzyme for the salvage pathway of nucleotide synthesis. Pemetrexed is a well-known anti-folate agent that inhibits the de novo pathway of nucleotide synthesis. Therefore, we hypothesized that tumors with MTAP gene loss have a synthetic lethality to pemetrexed due to loss of both essential nucleotide synthesis pathways. We proposed a study to determine pemetrexed response rate in patients with MTAP-deficient metastatic urothelial carcinoma (mUC). Methods: We carried out a single-arm, open-label, phase II clinical trial with pemetrexed in patients with mUC and MTAP loss by immunohistochemistry. This is an interim analysis of results. Each patient receives pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. Pemetrexed is continued until progression of disease (PD) and a repeat biopsy is obtained at that time. Pre- and post-treatment blood, urine and tumor samples are obtained for dynamic monitoring of immune and molecular correlates to clinical activity. Results: Six patients have been enrolled on this trial and all have received at least one previous treatment including a cisplatin-containing regimen in 5 (83%) patients and an immune checkpoint inhibitor in 4 (66%) patients. Of these 6 patients, 1 (17%) had complete response (CR); two (33%) had partial response (PR); 1 (17%) had stable disease; 1 (17%) was not evaluable; 1 (17%) had PD. Treatment was generally well tolerated with mostly grade 1 or 2 adverse events. Only 2 of 6 patients developed grade 3 anemia. Immunologic and molecular analyses are ongoing on all collected samples. Conclusions: Our study show that in heavily pretreated MTAP deficient mUC patients, pemetrexed is still an effective and well-tolerated therapy with an objective response rate (ORR=CR+PR) of 50%, which is higher than previously reported pemetrexed activity (ORR=8-28%) as first or second line treatment for mUC. Clinical trial information: NCT02693717.

A phase II study of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4509-4509 ◽  
Author(s):  
Xinan Sheng ◽  
Ai-Ping Zhou ◽  
Xin Yao ◽  
Yanxia Shi ◽  
Hong Luo ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
Locally Advanced ◽  
Visceral Metastasis ◽  
Her2 Positive ◽  
Metastatic Urothelial Carcinoma

4509 Background: Urothelial carcinoma (UC) is the third largest cancer type with HER2 positive cancer. RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). This study was to evaluate the activity of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma (mUC). Methods: This study is an open-label, multicenter, single-arm, non-randomized phase II study. Eligibility criteria include: histologically confirmed UC, HER2-positive (IHC 2+ or 3+), ECOG PS 0-1, treated with ≥1 prior systemic treatment. The patients received RC48-ADC treatment alone (2 mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary endpoint was objective response rate (ORR). Progress-free survival (PFS), overall survival (OS), and safety was also assessed. Results: Patient enrollment for this study was completed in November 2018. A total of 43 patients were enrolled, with a median age of 64 years old. At baseline, most patients (37/43) had visceral metastasis. Fourteen (32.6%) patients had received ≥ 2 lines treatment and 8 (18.6%) patients had prior immune checkpoint inhibitor (CPI) therapy in second line treatment. The objective response rate was 60.5% (95% CI: 44.4%, 75.0%) and the DCR was 90.7% (39/43). As of Jan 23, 2019, the median PFS for the overall study population was not yet reached, and the median PFS was 7.8 months (95% CI: 4.9, 10.7) for the 9 patients who started RC48-ADC prior to Jun 30, 2018. The ORR was 70.6% (12/17) in patients with HER2 FISH+ or IHC3+. The ORR was 64.9% (24/37) in patients with visceral metastasis and was 70.0% (14/20) in liver metastasis patients especially. The ORR was 64.3% in patients post to ≥ 2 lines treatment and 75.0% in patients post to immunotherapy. Common treatment-related AEs were leukopenia (51.2%), hypoesthesia (41.9%), alopecia (41.9%), neutropenia (37.2%), fatigue (34.9%), ALT increase (32.6%), and AST increase (32.6%); Most were Grade 1 or 2. Conclusions: RC48-ADC has demonstrated a clinically meaningful ORR of 60.5% in pretreated HER-2 positive mUC patients including those who underwent failure to the immunotherapy. Clinical trial information: NCT03507166.

Dual immune checkpoint blockade in advanced well-differentiated neuroendocrine tumors, a phase II clinical trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16201-e16201
Author(s):  
Susan Combs Scott ◽  
Ana De Jesus-Acosta ◽  
Chen Hu ◽  
Benjamin Philip Levy ◽  
Valsamo Anagnostou ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Neuroendocrine Tumors ◽  
Phase Ii ◽  
Median Duration ◽  
Primary Endpoint ◽  
Response Rate ◽  
Objective Response ◽  
Phase Ii Clinical Trial ◽  
Open Label ◽  
Well Differentiated

e16201 Background: Limited systemic treatment options are available for progressive well-differentiated neuroendocrine tumors (NET), also called carcinoid tumors. Given emerging evidence for immunotherapy response in high grade NET including small cell lung cancer, we sought to determine the efficacy of combination immunotherapy with ipilimumab and nivolumab in patients with advanced, progressive, well-differentiated NET in an open label phase II clinical trial. Methods: Eligible patients had well-differentiated, nonfunctional NET of lung, pancreas, or GI origin that had progressed within the past 12 months after at least one line of prior therapy. Patients received nivolumab 240 mg every 2 weeks and ipilimumab 1mg/kg every 6 weeks for up to 2 years. Primary endpoint was objective response rate (ORR) by RECIST v1.1. Using a Simon’s 2-stage design, the study planned to accrue up to 56 patients. Based on published response rates to everolimus of 5%, we hypothesized that this regimen would be considered promising if the true ORR is > 15%. Results: Nine patients were enrolled prior to study closure due to funding, including 6 patients with NET of lung origin, 2 pancreatic, and 1 small bowel (Table). Median age was 71 years. All patients had distant metastatic disease at enrollment, with an average of 2 prior lines of therapy. Four of 9 patients achieved the primary endpoint of confirmed objective response, all of whom have ongoing response with a median duration of 15.4 months. Five of 9 patients, including all 4 responders, experienced immune-related toxicity requiring treatment modification or discontinuation. The trial did not accrue the target of 56 patients, however, objective response in 4 of 9 patients (ORR 44.4%, 90% CI: 16.9-74.9%) excluded the response rate target (15%). Conclusions: The impressive ORR of 44% with a median duration of response exceeding 15 months in this small clinical trial warrants further study of combination CTLA-4 and PD-1 inhibition in previously treated well-differentiated NET. Our ongoing immunologic and genomic correlative analysis in responders and non-responders will help inform future study of immunotherapy in this patient population in need of new systemic therapy approaches. Clinical trial information: NCT03420521. [Table: see text]

scholarly journals Phase II California Cancer Consortium Trial of Gemcitabine-Eribulin Combination in Cisplatin-Ineligible Patients With Metastatic Urothelial Carcinoma: Final Report (NCI-9653)

2019 ◽  
Vol 37 (29) ◽  
pp. 2682-2688 ◽  
Author(s):  
Sarmad Sadeghi ◽  
Susan G. Groshen ◽  
Denice D. Tsao-Wei ◽  
Rahul Parikh ◽  
Amir Mortazavi ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Performance Status ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Median Number ◽  
Final Report ◽  
Curative Surgery ◽  
Metastatic Urothelial Carcinoma

PURPOSE Patients with metastatic urothelial carcinoma are often ineligible for cisplatin-based treatments. A National Cancer Institute Cancer Therapy Evaluation Program–sponsored trial assessed the tolerability and efficacy of a gemcitabine-eribulin combination in this population. METHODS Patients with treatment-naïve advanced or recurrent metastatic urothelial carcinoma of the bladder, ureter, or urethra not amenable to curative surgery and not candidates for cisplatin-based therapy were eligible. Cisplatin ineligibility was defined as creatinine clearance less than 60 mL/min (but ≥ 30 mL/min), grade 2 neuropathy, or grade 2 hearing loss. Treatment was gemcitabine 1,000 mg/m2 intravenously followed by eribulin 1.4 mg/m2, both on days 1 and 8, repeated in 21-day cycles until progression or unacceptable toxicity. A Simon two-stage phase II trial design was used to distinguish between Response Evaluation Criteria in Solid Tumors, version 1.1 objective response rates of 20% versus 50%. RESULTS Between June 2015 and March 2017, 24 eligible patients with a median age of 73 years (range, 62 to 88 years) underwent therapy. Performance status of 0, 1, or 2 was seen in 11, 11, and two patients, respectively. Sites of disease included: lymph nodes, 16; lungs, nine; liver, seven; bladder, five; bones, two. Median number of cycles received was four (range, one to 16). Of 24 patients, 12 were confirmed responders; the observed objective response rate was 50% (95% CI, 29% to 71%). Median overall survival was 11.9 months (95% CI, 5.6 to 20.4 months), and median progression-free survival was 5.3 months (95% CI, 4.5 to 6.7 months). The most common treatment-related any-grade toxicities were fatigue (83% of patients), neutropenia (79%), anemia (63%), alopecia (50%), elevated AST (50%), and constipation, nausea, and thrombocytopenia (42% each). CONCLUSION Gemcitabine-eribulin treatment response and survival for cisplatin-ineligible patients compare favorably to other regimens. Additional research is needed.

Response to second-line chemotherapy (Ctx) in advanced urothelial carcinoma: A pooled retrospective analysis of the correlation between objective response rate (ORR) and progression-free survival (PFS) and overall survival (OS).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 354-354
Author(s):  
Anuradha Jayaram ◽  
MinYuen Teo ◽  
Raymond S. McDermott
Keyword(s):  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Survival Benefit ◽  
Response Rate ◽  
Pearson Correlation ◽  
Objective Response ◽  
Response Rates ◽  
Second Line ◽  
Advanced Urothelial Carcinoma ◽  
Combination Regimens

354 Background: Second-line ctx for advanced urothelial carcinoma (UC) constitutes a substantial unmet need. A commonly used endpoint in phase II studies is ORR, however it is unclear whether this translates to a benefit in OS and PFS. We previously examined pooled OS, PFS, ORR and DCR in second line ctx in advance UC. We now are now determining whether increased ORR correlates with improved PFS and OS. Methods: Published second-line studies were identified from PubMed between 1997- 2012 and were reviewed for data extraction. Pearson correlation coefficient was used to determine correlation between ORR and OS and PFS. Results: 25 prospective studies of second-line ctx for progressive advanced UC were identified (22 non-randomised, 3 randomised) (n= 1,297). The majority of studies (88%) were phase II. 12 studies investigated combination regimens and 13 studies monotherapy. All studies allowed adjuvant and primary chemotherapy as first-line but only 7 studies reported median time from last chemotherapy. The range of reported response rates were 1% - 29%. ORR is moderately correlated to PFS (r= 0.42 {0.01 - 0.71} p = 0.04) and OS (r=0.67 {0.39 - 0.84} p = <0.01) in the entire cohort. When we compared the combination regimens to monotherapy the ORR was 27.7% versus 12.3% (p<0.01). The reported response rate for monotherapy was 8.6% - 27.7% and there was no correlation between ORR and PFS (r=0.26 {-0.37 - 0.72} p=0.42) and OS (r = 0.35 {-0.25 - 0.76} p=0.24). Conversely with combination regimens, response rates were 7% - 60% and ORR strongly correlated to PFS (r= 0.78 {0.40 - 0.93} p =<0.001) and OS (r=0.80 {0.43 - 0.94}, p=<0.001). Conclusions: The analysis revealed that ORR translated to a survival benefit. In second line ctx for advanced UC, responses to combination therapy only yielded a survival benefit. This may be appropriate approach in patients with a good performance status.

A randomized phase II study of pelareorep (REO) plus docetaxel vs. docetaxel alone in patients with metastatic castration resistant prostate cancer (mCRPC): Canadian Cancer Trials Group study IND 209.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5021-5021 ◽  
Author(s):  
Bernhard J. Eigl ◽  
Eric Winquist ◽  
Dongsheng Tu ◽  
Sebastien J. Hotte ◽  
Christina M. Canil ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Prognostic Score ◽  
Objective Response ◽  
Prognostic Index ◽  
Dose Intensity ◽  
Biomarker Analysis

5021 Background: Pelareorep (REO) is an oncolytic virus with in vitro and in vivo activity in many cancers, including prostate. It has in vitro synergism with microtubule targeted agents especially taxanes. We undertook a clinical trial to evaluate REO in mCRPC patients (pts) receiving docetaxel. Methods: In this randomized, open-label multicenter phase II study, pts received docetaxel 75mg/m2 on day 1 of a 21-day cycle in combination with REO given as 3x1010 TCID50 IV daily on days 1-5 (arm A), or alone (arm B). The primary endpoint was 12-week lack of disease progression (LPD) rate. Secondary endpoints included objective response rate; survival; circulating tumor cell (CTC) enumeration at 0, 6 and 12 weeks; PSA response rate and biomarkers. Results: Eighty-five pts were randomized. Median age was 69, ECOG performance status (PS) was 0/1/2 in 31%/66%/3% of pts. Bone/regional lymph node/liver metastases were present in 98%/24%/6% of pts. More pts in arm A had poor prognostic factors for survival at baseline (median prognostic index 1.44 vs. 1.29). The median number of cycles delivered for arms A/B was 7/9 (range 1-10 and 1-13). In arm A, 51%/68% of pts received ≥90% of planned dose intensity of docetaxel/REO respectively, vs. 76% of pts for docetaxel in arm B. Adverse events (AE) were as expected for docetaxel therapy but more prevalent in arm A (grade 3 or higher all AEs 80 vs. 74%). A higher rate of grade 4 febrile neutropenia was noted in arm A (7 vs. 0%) but may represent virus related fevers. The 12-week LPD rate was 61% and 52.4% in A/B respectively (p = 0.51). OS was worse in arm A vs. B (HR 1.95; 95% CI 0.94-4.06; p = 0.07 after adjusting for age, PS and baseline prognostic score). There was no difference between arms in CTC favourable status at any timepoint. No survival benefit of REO with D was found in any subset from the biomarker analysis. Conclusions: While the combination of REO with D for patients with mCRPC was tolerable and LPD rate was comparable in both arms, docetaxel dose intensity and survival were inferior and so this combination, as tested, does not merit further study. Clinical trial information: NCT01619813.

Recombinant humanized anti-PD-1 monoclonal antibody toripalimab in patients with metastatic urothelial carcinoma: Results of an open-label phase II clinical study Polaris-03.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5040-5040
Author(s):  
Xinan Sheng ◽  
Haige Chen ◽  
Bin Hu ◽  
Xudong Yao ◽  
Ziling Liu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Study ◽  
Urothelial Carcinoma ◽  
Clinical Response ◽  
Disease Progression ◽  
Phase Ii ◽  
Safety Profile ◽  
Clinical Activity ◽  
Phase Ii Clinical Study ◽  
Metastatic Urothelial Carcinoma

5040 Background: Patients with advanced metastatic urothelial carcinoma (UC) who experience disease progression after standard therapy have limited treatment options. Phase I study of toripalimab in subjects with heavily pretreated metastatic UC had demonstrated an acceptable safety profile and promising clinical activity. Here we report the safety and efficacy result of toripalimab in a phase II clinical study (POLARIS-03) in Chinese patients with metastatic urothelial carcinoma. (Clinical trial ID: NCT03113266). Methods: Metastatic UC Patients receive toripalimab 3 mg/kg Q2W until disease progression, unacceptable toxicity or voluntary withdrawal. Clinical response is assessed every 8 weeks. Tumor PD-L1 expression and other biomarkers will be evaluated for correlation with clinical response. Results: From May 2017 to September 2019, 204 patients were screened and the study enrollment was completed with 151 patients enrolled from 15 participating centers. The median age was 62 years and 66% were male. 87% patients had visceral metastasis. By the cut-off date of Jan 6, 2020, 92.1% (139/151) patients experienced treatment related adverse event (TRAE) and grade 3 and above TRAE occurred in 35.8% (54/151) patients. Most common TRAE included anemia, triglycerides increased, proteinuria, fatigue, and hyperglycemia. Treatment discontinuation due to a TRAE occurred in 6 (4.0%) patients, while dose delay due to a TRAE occurred in 23 (15.2%) patients. Three patients with major protocol deviations were excluded from efficacy analysis. Among 148 patients assessed by IRC per RECISTv1.1, 2 CR, 36 PR, and 30 SD were observed for an ORR of 25.7% and a DCR of 45.9%. The median DOR was 15.7 months. The median PFS was 1.9 months, and the median OS was estimated 20.8 months. PD-L1 expression results were obtained from 141 patients. PD-L1+ patients (n=46) had significant better ORR than PD-L1- patients (n=95), 41.3% versus 16.8% ( p<0.01). Conclusions: Toripalimab has demonstrated encouraging clinical activity in chemo-refractory UC patients with a manageable safety profile. Patients will be continuously monitored for safety and overall survival. Clinical trial information: NCT03113266 .

A randomized phase II trial of cabozantinib combined with PD-1 and CTLA-4 inhibition in metastatic soft tissue sarcoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS11583-TPS11583
Author(s):  
Vanessa Anne Eulo ◽  
Breelyn A. Wilky ◽  
Jingqin Luo ◽  
Angela C. Hirbe ◽  
Mia C. Weiss ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Soft Tissue ◽  
Phase Ii ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
Soft Tissue Sarcomas ◽  
Randomized Phase Ii ◽  
Metastatic Setting

TPS11583 Background: Soft tissue sarcomas (STS) are rare malignancies with poor prognosis in the metastatic setting. Current standard therapy includes anthracycline based chemotherapy. Cabozantinib is a multikinase inhibitor that has demonstrated efficacy in solid tumors such as renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). A phase II study of cabozantinib in advanced STS is underway. Cabozantinib in combination with immune checkpoint blockade has shown clinical benefit in several tumor types including HCC, RCC, non-small cell lung cancer, and urothelial carcinoma. Since cabozantinib may alter PD-1 expression in regulatory T-cells and promote an immune permissive environment, we hypothesize that combining cabozantinib with immune checkpoint inhibition is a therapeutic strategy that will be more effective than cabozantinib alone. Additionally, the design of the trial will allow assessment of whether pretreatment with cabozantinib will enhance the efficacy of nivolumab and ipilimumab alone. Methods: This is an open label, multicenter, randomized phase II clinical trial of cabozantinib (60mg orally daily as a single agent, 40mg in combination) with or without combination Ipilimumab (ipi, 1mg/kg IV every 3 weeks for 4 doses) and Nivolumab (nivo, 3mg/kg IV every 3 weeks for four doses, then 480mg IV every 4 weeks) in patients (pts) with unresectable or metastatic STS refractory to up to two lines of chemotherapy. 105 pts with non-translocation driven sarcomas will be enrolled at three US sites and randomized 2:1 to the combination group. Pts will be stratified by prior pazopanib use and balanced for histologies. Patients who progress on arm A will cross over to combination therapy (arm B). The primary efficacy endpoint is objective response rate (ORR) by RECIST 1.1. 35 patients in Cohort A (cabozantinib alone) and 70 patients in Cohort B (cabozantinib plus ipi/nivo) will be required to detect an increase of the ORR from 10% in cohort A to 30% in cohort B with 81% power with a one-sided alpha level of 10%. Key eligibility criteria include: at least 18 years of age, ECOG performance status of 0 or 1, ≤2 prior lines of therapy and measurable disease. Exclusion criteria include: translocation-driven sarcoma except alveolar soft part sarcoma (ASPS), prior immunotherapy, and chronic use of corticosteroids or other immunosuppression. Secondary endpoints are safety, overall and progression free survival, disease control rate, and response rate to ipilimumab and nivolumab after cabozantinib pretreatment. Mandatory tumor biopsies pre-treatment and at 6 weeks will be obtained. Peripheral blood will be collected for circulating immune phenotyping. Enrollment will occur at 3 participating institutions and is expected to be completed in 2022. Clinical trial information: NCT04551430.

scholarly journals A Phase II Clinical Trial of TRC105 (Anti-Endoglin Antibody) in Adults With Advanced/Metastatic Urothelial Carcinoma

2017 ◽  
Vol 15 (1) ◽  
pp. 77-85 ◽  
Author(s):  
Andrea B. Apolo ◽  
Fatima H. Karzai ◽  
Jane B. Trepel ◽  
Sylvia Alarcon ◽  
Sunmin Lee ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Phase Ii Clinical Trial ◽  
Metastatic Urothelial Carcinoma

Trial in progress: A phase 1b/2 study of the PARP inhibitor niraparib in combination with trastuzumab in patients with metastatic HER2+ breast cancer (TBCRC 050).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1098-TPS1098
Author(s):  
Erica Michelle Stringer-Reasor ◽  
Yufeng Li ◽  
Felicia Witherspoon ◽  
Jennifer M. Specht ◽  
Jesus Del Santo Anampa Mesias ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Dna Repair ◽  
Response Rate ◽  
Synthetic Lethality ◽  
Objective Response ◽  
Parp Inhibitors ◽  
Response To Therapy ◽  
Her2 Breast Cancer ◽  
Phase 1B

TPS1098 Background: Approximately 20% of breast cancers (BC) express the human epidermal growth factor receptor 2 (HER2). Although HER2-directed therapies result in improved patient outcome, resistance ultimately occurs. Poly (ADP-Ribose) polymerase (PARP) inhibitors are currently indicated in cancers that express germline mutations in the DNA repair proteins BRCA1/2 due to their synthetic lethality against the homologous recombination repair (HR) pathway. In addition to its role in DNA damage repair, PARP1 has also been implicated in other cellular functions, including co-activation of genes such as NF-κB, which regulate tumor proliferation and HER2 drug resistance. Our group identified that HER2+ BC overexpress the PARP1 and phospho-p65 protein. In HER2+ BC cells and animal models, PARP inhibitors initiated apoptosis independent of a DNA repair deficiency, via inhibition of NF-kB signaling. Key proteins (p65, IKK-α) of the NF-κB-mediated growth pathways were reduced and IκBα was increased in the presence of PARPi, implicating another oncologic pathway in which HER2+ BC cells may be dependent. Methods: The study is a phase 1b/2, multicenter, single arm clinical trial evaluating the safety and efficacy of niraparib 200 mg orally days 1-21 with trastuzumab 6 mg/kg (cycle 1 loading dose of 8 mg/kg) intravenously on day 1 of a 21-day cycle for patients with unresectable or metastatic HER2+ BC. Eligible patients include metastatic HER2+ BC, progression on at least 1 prior HER2-targeted therapy, measurable disease, ECOG PS 0-1, and LVEF ≥ 50%. Stable/treated CNS disease allowed. Prior PARPi and known germline BRCA 1/2 excluded. Forty patients will be enrolled at 7 US sites within the Translational Breast Cancer Research Consortium. The primary objectives are determining the dose-limiting toxicity (DLT) of the combination and assessing the objective response rate. The phase 1b cohort has been completed (N=6). Enrollment in phase 2 began February 2021 with a total accrual goal of 40. Gehan’s two-stage design will be used assuming the response rate is at least 24% and the response rate will be estimated with Clopper-Pearson exact method. Correlative aims include assessing blood and tissue biomarkers (e.g. PARP1, p65, phosphor-p65, let-7a miRNA, NF-kB, ctDNA, etc.) for association with clinical benefit and to predict response to therapy. Clinical trial information: NCT03368729 .

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