Spots Global Cancer Trial Database for Nadunolimab in Combination With Gemcitabine Plus Carboplatin in Patients With Advanced Triple Negative Breast Cancer.

Study Description

Brief Summary: Triple negative breast cancer (TNBC) represents approximately 15% of all breast cancers (BC) worldwide. The term triple negative means that tumor growth is not stimulated by the hormones estrogen and progesterone, nor by the HER2 protein, so unlike other types of BC, TNBC, which is an aggressive form of BC, does not have specific effective therapies available being the least common form of BC and the most difficult to treat. Advanced or metastatic TNBC is treated with combinations of platinum-based chemotherapy with taxanes or gemcitabine with a 5-year survival rate of 12%. Recent studies have shown that TNBC expresses Interleukin 1 Receptor Accessory Protein (IL1RAP) at higher levels than other forms of BC. Nadunolimab is a fully humanized monoclonal antibody that blocks the signals that occur within the cell produced by IL1RAP protein, thereby impairing the cancer cells' ability to secrete tumor stimulating substances, in turn reducing the tumor, inflammation and tumor progression. On the other hand, it is an antibody designed to activate the immune system to fight cancer cells. This clinical trial is divided into two phases, phase Ib in which it is expected to include up to 18 patients and phase II in which it is expected to include 98 patients. The main purpose of phase Ib is to ensure that the combination of nadunolimab plus chemotherapy (gemcitabine plus carboplatin) is safe and determine the highest dose of nadunolimab that can be given safely without causing serious side effects. If the pre-specified objectives in this part are achieved, the trial will be expanded to a randomized phase II, to evaluate the efficacy of the combination of nadunolimab plus gemcitabine plus carboplatin, compared to a control group that will receive gemcitabine plus carboplatin only.

Detailed Description: Triple negative breast cancer (TNBC) represents approximately 15% of all breast cancers worldwide and is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. TNBC is more common in African American women, in premenopausal women and in BRCA1/2 mutation carriers. TNBC presents the worst outcomes of all breast cancer (BC) subtypes with a 5-year overall survival (OS) of 78.5%, even when the analyses are adjusted for age, disease stage, race, tumor grade and adjuvant chemotherapy (CT). One in three TNBC patients will develop distant metastases, which typically occurs within the first 3 years of initial diagnosis, and persistently, one in five TNBC patients will succumb to their metastatic disease in less than 5 years. The 5-year survival rates for localized, regional, and metastatic TNBC are 91%, 65%, and 12% , respectively. The dismal prognosis of high-risk, locally advanced and metastatic TNBC highlights an unmet need for an improved survival in these patients. Another reason for the poor outcomes associated with TNBC is the lack of effective targeted therapies. As a result, standard cytotoxic CT remains the backbone of systemic therapy in TNBC patients. Further attempts to classify TNBC into distinct subtypes based on unique tumor/tumor microenvironment (TME) cellular signatures and messenger ribonucleic acid (mRNA) expression profiles may provide relevant information about the molecular drivers, actionable therapeutic targets and effective therapy selection. Based on the PAM50 gene expression profile, 78.6% of TNBC have significant overlap with the basal-like molecular subtype. The remaining gene expression profiles of TNBC (21.4%) may be further subclassified as normal-like (7%), HER2-enriched (7.8%), luminal B (4.4%), and luminal A (2.2%). Even though the assessment and characterization of TNBC into molecular subtypes is not currently performed clinically on a routine basis, these sub-classifications based on unique cellular signatures and global RNA expression profiles may provide therapeutic insights for each specific subset of TNBC patients. Current available treatments for advanced TNBC are palliative in nature and are based mostly on the use of cytotoxics. Recently poly Adenosine diphosphate (ADP) ribose polymerase inhibitors (PARPi), (olaparib, talazoparib) have shown efficacy in patients with germline BRCA (gBRCA) mutant tumors, with olaparib and talazoparib already approved in the advanced setting. Atezolizumab in combination with nab-paclitaxel has been approved for patients with unresectable locally advanced or metastatic TNBC whose tumors express programmed death-ligand 1 (PD-L1). Pembrolizumab, in combination with CT (paclitaxel, or nab-paclitaxel, or gemcitabine plus carboplatin), has been granted accelerated approval by the Food and Drug Administration (FDA) for locally recurrent unresectable or metastatic TNBC not previously treated with CT in the metastatic setting and with PD-L1 expression (Combined Positive Score (CPS) ≥ 10) as determined by the PD-L1 immunohistochemistry (IHC) 22C3 pharmDx (Dako North America, Inc.), also approved by the FDA as a companion diagnostic. Despite of these interesting results, new treatments are necessary for patients with TNBC. Platinum agents have recently become an important treatment option in the management of TNBC, especially in patients with BRCA mutations or PD-L1-negative or who have progressed to immune checkpoint inhibitors, as carboplatin demonstrated comparable efficacy and a more favorable toxicity profile compared with docetaxel. Platinum-based regimens are particularly appealing in TNBC based on their DNA-damaging mechanism of action , due to the high genomic instability observed on this type of BC, particularly in patients harbouring gBRCA1/2 mutations or "BRCAness" (homologous recombination repair defects in the absence of gBRCA1/2 mutations). The TNT trial showed that carboplatin is a particularly active drug in gBRCA mutated BC patients. In the metastatic setting, interesting activity has been reported with the gemcitabine plus carboplatin combination (dose of 1,000 mg/m2 and area under the curve \[AUC\] 2 mg x min/mL, respectively, on days 1 and 8 of each 3-week cycle), in both phase II and III trials testing the role of iniparib in advanced TNBC with a median progression-free survival (PFS) of 3.1 and 4.1 months, and a median OS of 7.7 and 11.1 months, respectively. In exploratory analyses by line of therapy in the phase III trial, patients who received first line treatment had a median PFS of 4.6 months and a median OS of 12.6 months; for those patients treated in second line, the median PFS was 2.9 months and the median OS was 8.1 months. Regarding the tumor response according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 with confirmation of response and independent central review, the following percentages were reported: a) complete response (CR) 1.6%; b) partial response (PR) 29%; c) stable disease (SD) 35% (lasting more than 6 months in 5.4%); d) progressive disease (PD) 24%; and e) nonevaluable 5.4%. The overall response rate (ORR) was 30% (95% Confidence Interval (CI), 25-36%) and the clinical benefit rate (CBR) with SD \> 6 months, 36%. If we consider the Treatment Emergent Adverse Events (TEAEs) published in 2014, the most frequent AEs included neutropenia 65% (Grade \[G\] 3/4 53%), fatigue 63% (G 3/4 6%), anemia 62% (G 3/4 22%), nausea 59% (G 3/4 3%), thrombocytopenia 54% (G 3/4 24%), constipation 42% (G 3/4 \< 1%), and vomiting 31% (G 3/4 1%). Data from the tnAcity trial in the first line setting showed a median PFS of 6.0 months and a median OS of 12.6 months in the control arm treated with gemcitabine 1,000 mg/m2 plus carboplatin AUC 2 mg x min/mL, on days 1 and 8 of 3-week cycles. Another efficacy results published include the 12-month PFS rate (11%), ORR (44% \[CR 8%, PR 36%\]), median duration of response (DoR) (5.0 months), SD ≥ 4 months (32%), PD as best response (21%). At least one G ≥ 3 AE was reported in 84% of patients and at least one serious AE in 39% of patients with this combination. The most frequently observed G ≥ 3 AEs were neutropenia (52%), thrombocytopenia (28%), anemia (27%), leukopenia (11%), fatigue (3%) and peripheral neuropathy (2%). The meta-analysis with data from more than 4,500 patients supports the use of platinums in Advanced Breast Cancer (ABC) and this recommendation is considered in current international practice guidelines ABC.

Keywords

Eligibility

Minimum Age: 18 Years

Eligible Ages: ADULT, OLDER_ADULT

Sex: ALL

Healthy Volunteers: No

Locations

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