MGC018 for Small Cell Lung Cancer
(MGC018-SCLC Trial)
Recruiting in Palo Alto (17 mi)
+3 other locations
Overseen byChul Kim, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Georgetown University
Must not be taking: Investigational agents
Disqualifiers: Leptomeningeal disease, Other malignancy, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?The goal of this clinical trial is to test MGC018 in patients with relapsed or refractory Extensive-Stage Small-Cell Lung Cancer (ES-SCLC). The main question it aims to answer is:
• Does the administration of MGC018 achieve a clinically meaningful response rate of 25% in patients with relapsed or refractory ES-SCLC?
Participants enrolled in the trial will receive MGC018 through an intravenous (IV) infusion, every 28 days until disease progression or unacceptable toxicity. Tumor assessment will be done every 2 cycles (28 day cycles). Blood samples will be taken for biomarker analysis before treatment, on cycle 3 day 1, and at progression. A pretreatment biopsies will be done.
Do I need to stop my current medications for the trial?
The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on other investigational agents, you cannot participate in this trial.
What data supports the effectiveness of the drug MGC018, Vobramitamab Duocarmazine, for treating small cell lung cancer?
While there is no direct data on MGC018, Vobramitamab Duocarmazine for small cell lung cancer, similar treatments like lorvotuzumab mertansine have shown promising results in targeting specific proteins on cancer cells, leading to significant tumor reduction in preclinical models. This suggests that targeted therapies can be effective against small cell lung cancer.
12345What makes the drug MGC018 unique for treating small cell lung cancer?
MGC018, also known as Vobramitamab Duocarmazine, is unique because it is an antibody-drug conjugate, which means it combines an antibody with a drug to specifically target and kill cancer cells. This targeted approach is different from traditional chemotherapy, which affects both cancerous and healthy cells.
26789Eligibility Criteria
This trial is for people with Extensive-Stage Small-Cell Lung Cancer (ES-SCLC) that has come back or hasn't responded to treatment. Participants will receive MGC018 every 28 days via IV until their disease worsens or the side effects become too much.Inclusion Criteria
Ability to understand and the willingness to sign a written informed consent document
My small cell lung cancer is advanced and cannot be treated with surgery or radiation meant to cure.
I can provide a recent biopsy of my tumor.
+8 more
Exclusion Criteria
I don't have any health issues that would make it unsafe for me to take a new drug.
Patient who are receiving any other investigational agents
I have had leptomeningeal disease.
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive MGC018 through an intravenous (IV) infusion every 28 days until disease progression or unacceptable toxicity
Approximately 1 year
1 visit every 28 days (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
60 days after last treatment
Long-term follow-up
Overall survival is assessed from study drug initiation to death
3 years
Participant Groups
The study tests if MGC018 can help at least 25% of patients whose ES-SCLC has relapsed or is refractory. It involves regular tumor assessments and blood tests for biomarkers before and during treatment, as well as after disease progression.
1Treatment groups
Experimental Treatment
Group I: MCG018Experimental Treatment1 Intervention
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Medstar Washington Hospital CenterWashington, United States
Lombardi Comprehensive Cancer Center, Georgetown UniversityWashington, United States
The Harry and Jeanette Weinberg Cancer Institute at MedStar Franklin Square Medical CenterBaltimore, MD
Hackensack Meridian Health, John Theurer Cancer CenterHackensack, NJ
Loading ...
Who Is Running the Clinical Trial?
Georgetown UniversityLead Sponsor
MacroGenicsIndustry Sponsor
References
Safety, pharmacokinetics, and efficacy of budigalimab with rovalpituzumab tesirine in patients with small cell lung cancer. [2022]Agents targeting programmed cell death protein 1 (PD-1) have been approved as monotherapy for patients with small cell lung cancer (SCLC). In preclinical models, the combined targeting of PD-1 and delta-like protein 3 resulted in enhanced antitumor activity. Herein, we report results from the expansion arm of study NCT03000257 evaluating the combination of the anti-PD-1 antibody budigalimab and the targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T) in patients with previously treated SCLC.
Lorvotuzumab mertansine, a CD56-targeting antibody-drug conjugate with potent antitumor activity against small cell lung cancer in human xenograft models. [2021]Lorvotuzumab mertansine (LM) is an antibody-drug conjugate composed of a humanized anti-CD56 antibody, lorvotuzumab, linked via a cleavable disulfide linker to the tubulin-binding maytansinoid DM1. CD56 is expressed on most small cell lung cancers (SCLC), providing a promising therapeutic target for treatment of this aggressive cancer, which has a poor five-year survival rate of only 5-10%. We performed immunohistochemical staining on SCLC tumor microarrays, which confirmed that CD56 is expressed at high levels on most (~74%) SCLC tumors. Conjugation of lorvotuzumab with DM1 did not alter its specific binding to cells and LM demonstrated potent target-dependent cytotoxicity against CD56-positive SCLC cells in vitro. The anti-tumor activity of LM was evaluated against SCLC xenograft models in mice, both as monotherapy and in combination with platinum/etoposide and paclitaxel/carboplatin. Dose-dependent and antigen-specific anti-tumor activity of LM monotherapy was demonstrated at doses as low as 3 mg/kg. LM was highly active in combination with standard-of-care platinum/etoposide therapies, even in relatively resistant xenograft models. LM demonstrated outstanding anti-tumor activity in combination with carboplatin/etoposide, with superior activity over chemotherapy alone when LM was used in combinations at significantly reduced doses (6-fold below the minimally efficacious dose for LM monotherapy). The combination of LM with carboplatin/paclitaxel was also highly active. This study provides the rationale for clinical evaluation of LM as a promising novel targeted therapy for SCLC, both as monotherapy and in combination with chemotherapy.
Molecular Subtypes and Tumor Microenvironment Characteristics of Small-Cell Lung Cancer Associated with Platinum-Resistance. [2023]Although molecular subtypes of small-cell lung cancer (SCLC) have been proposed, their clinical relevance and therapeutic implications are not fully understood. Thus, we aimed to refine molecular subtypes and to uncover therapeutic targets. We classified the subtypes based on gene expression (n = 81) and validated them in our samples (n = 87). Non-SCLC samples were compared with SCLC subtypes to identify the early development stage of SCLC. Single-cell transcriptome analysis was applied to dissect the TME of bulk samples. Finally, to overcome platinum resistance, we performed drug screening of patient-derived cells and cell lines. Four subtypes were identified: the ASCL1+ (SCLC-A) subtype identified as TP53/RB-mutated non-SCLC representing the early development stage of SCLC; the immune activation (SCLC-I) subtype, showing high CD8+/PD-L1+ T-cell infiltration and endothelial-to-mesenchymal transition (EndMT); the NEUROD1 (SCLC-N) subtype, which showed neurotransmission process; and the POU2F3+ (SCLC-P) subtype with epithelial-to-mesenchymal transition (EMT). EndMT was associated with the worst prognosis. While SCLC-A/N exhibited platinum sensitivity, the EndMT signal of SCLC-I conferred platinum resistance. A BET inhibitor suppressed the aggressive angiogenesis phenotype of SCLC-I. We revealed that EndMT development contributed to a poor outcome in SCLC-I. Moreover, heterogenous TME development facilitated platinum resistance. BET inhibitors are novel candidates for overcoming platinum resistance.
Small cell lung cancer: will recent progress lead to improved outcomes? [2022]Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with a unique natural history characterized by a short doubling time, high growth fraction, and early development of widespread metastases. Although a chemotherapy- and radiation-sensitive disease, SCLC typically recurs rapidly after primary treatment, with only 6% of patients surviving 5 years from diagnosis. This disease has been notable for the absence of major improvements in its treatment: Nearly four decades after the introduction of a platinum-etoposide doublet, therapeutic options have remained virtually unchanged, with correspondingly little improvement in survival rates. Here, we summarize specific barriers and challenges inherent to SCLC research and care that have limited progress in novel therapeutic development to date. We discuss recent progress in basic and translational research, especially in the development of mouse models, which will provide insights into the patterns of metastasis and resistance in SCLC. Opportunities in clinical research aimed at exploiting SCLC biology are reviewed, with an emphasis on ongoing trials. SCLC has been described as a recalcitrant cancer, for which there is an urgent need for accelerated progress. The NCI convened a panel of laboratory and clinical investigators interested in SCLC with a goal of defining consensus recommendations to accelerate progress in the treatment of SCLC, which we summarize here.
Immune checkpoint blockade in small cell lung cancer: is there a light at the end of the tunnel? [2021]Small cell lung cancer (SCLC) is a very aggressive disease, characterised by rapid growth, high response rates to both chemotherapy and radiotherapy and subsequent development of treatment resistance in the vast majority of patients. In the past 30 years, little progress has been made in systemic treatments and the established management paradigm of platinum-based chemotherapy has reached an efficacy plateau. Several clinical trials have investigated targeted therapies, without producing clinically significant benefits. Recently presented early phase clinical trials with immune checkpoint inhibitors (blockade of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and blockade of the programmed cell death-1 (PD-1) receptor) have shown promising results. In this review, we present the emerging evidence on immune checkpoint blockade for SCLC.
Acquired small cell lung cancer resistance to Chk1 inhibitors involves Wee1 up-regulation. [2022]Platinum-based chemotherapy has been the cornerstone treatment for small cell lung cancer (SCLC) for decades, but no major progress has been made in the past 20 years with regard to overcoming chemoresistance. As the cell cycle checkpoint kinase 1 (Chk1) plays a key role in DNA damage response to chemotherapeutic drugs, we explored the mechanisms of acquired drug resistance to the Chk1 inhibitor prexasertib in SCLC. We established prexasertib resistance in two SCLC cell lines and found that DNA copy number, messengerRNA (mRNA) and protein levels of the cell cycle regulator Wee1 significantly correlate with the level of acquired resistance. Wee1 small interfering RNA (siRNA) or Wee1 inhibitor reversed prexasertib resistance, whereas Wee1 transfection induced prexasertib resistance in parental cells. Reverse phase protein microarray identified up-regulated proteins in the resistant cell lines that are involved in apoptosis, cell proliferation and cell cycle. Down-regulation of CDK1 and CDC25C kinases promoted acquired resistance in parental cells, whereas down-regulation of p38MAPK reversed the resistance. High Wee1 expression was significantly correlated with better prognosis of resected SCLC patients. Our results indicate that Wee1 overexpression plays an important role in acquired resistance to Chk1 inhibition. We also show that bypass activation of the p38MAPK signaling pathway may contribute to acquired resistance to Chk1 inhibition. The combination of Chk1 and Wee1 inhibitors may provide a new therapeutic strategy for the treatment of SCLC.
Novel therapies for the treatment of small-cell lung cancer: a time for cautious optimism? [2018]Small-cell lung cancer accounts for up to one-fifth of all lung cancers diagnosed. While the response rates to chemotherapy are high, ultimately the majority of patients will relapse and die from their disease. Long-term outcomes are poor. A number of new agents and novel strategies for the treatment of small-cell lung cancer are under evaluation, and this review outlines the current most promising agents and pivotal trials. Oblimersen, an antisense oligonuclide to the oncogene bcl-2, has been safely combined with chemotherapy. The proteosome inhibitor bortezomib has not demonstrated single-agent activity in phase II trials but is now being evaluated with proapoptotic triggers. A number of anti-angiogenic strategies have been evaluated in small-cell lung cancer. The vascular endothelial growth factor (VEGF) antibody bevacizumab and a number of VEGF receptor tyrosine kinase inhibitors are in the early phases of clinical trials. Results from trials have not demonstrated any survival advantage with the addition of matrix metalloproteinase inhibitors. A phase III trial has reported improvements in median survival with the addition of thalidomide to chemotherapy, but toxicity has been problematic. Immunotherapy with p53 vaccines and BEC2 antibodies have shown some promise and require further evaluation to determine whether humoral responses can predict for response. Trials with the immunoconjugate BB-10901 and temirolimus are ongoing.
Phase I study of MG98, an oligonucleotide antisense inhibitor of human DNA methyltransferase 1, given as a 7-day infusion in patients with advanced solid tumors. [2017]To assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of MG98, an antisense oligonucleotide to DNA methyltransferase 1 (DNMT1), which has been shown to reduce CpG island methylation and allow reexpression of tumor suppressor genes in vitro.
Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer. [2022]Nearly all patients with small cell lung cancer (SCLC) eventually relapse with chemoresistant disease. The molecular mechanisms driving chemoresistance in SCLC remain un-characterized. Here, we describe whole-exome sequencing of paired SCLC tumor samples procured at diagnosis and relapse from 12 patients, and unpaired relapse samples from 18 additional patients. Multiple somatic copy number alterations, including gains in ABCC1 and deletions in MYCL, MSH2, and MSH6, are identifiable in relapsed samples. Relapse samples also exhibit recurrent mutations and loss of heterozygosity in regulators of WNT signaling, including CHD8 and APC. Analysis of RNA-sequencing data shows enrichment for an ASCL1-low expression subtype and WNT activation in relapse samples. Activation of WNT signaling in chemosensitive human SCLC cell lines through APC knockdown induces chemoresistance. Additionally, in vitro-derived chemoresistant cell lines demonstrate increased WNT activity. Overall, our results suggest WNT signaling activation as a mechanism of chemoresistance in relapsed SCLC.