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DRUG:

nibrozetone (RRx-001)

i
Other names: RRx-001, ABDNAZ, RRx 001, R001, R 001, R-001, RRx001
Company:
EpicentRx, SciClone
Drug class:
CD47 inhibitor, MYC inhibitor, NLRP3 inhibitor, NRF2 activator, SIRPA antagonist
Related drugs:
10d
Phase classification • Metastases
|
cisplatin • nibrozetone (RRx-001)
14d
Enrollment closed
|
cisplatin • carboplatin • etoposide IV • nibrozetone (RRx-001)
4ms
PIRATE: RRx-001 Given With Irinotecan and Temozolomide for Pediatric Patients With Recurrent or Progressive Malignant Solid and Central Nervous System Tumors (clinicaltrials.gov)
P1, N=2, Terminated, EpicentRx, Inc. | N=24 --> 2 | Trial completion date: Dec 2024 --> Jul 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Jul 2024; Low Enrollment
Enrollment change • Trial completion date • Trial termination • Trial primary completion date • Combination therapy
|
temozolomide • irinotecan • nibrozetone (RRx-001)
5ms
CD40 agonist engineered immunosomes modulated tumor microenvironment and showed pro-immunogenic response, reduced toxicity, and tumor free survival in mice bearing glioblastoma. (PubMed, Biomaterials)
To overcome these issues, in this study, we have developed a multifunctional Immunosome where αCD40 is conjugated on the surface and RRX-001, a small molecule immunomodulator was encapsulated inside it...In addition, Immunosomes treated long-term surviving mice showed tumor specific immune memory response which prevented tumor growth upon rechallenge. Our results suggested that this novel formulation can be further explored in clinics to improve in vivo anti-tumor efficacy of αCD40 with long-lasting tumor specific immunity while reducing the associated toxicities.
Preclinical • Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD20 (Membrane Spanning 4-Domains A1) • CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • IL6 (Interleukin 6) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • IL2 (Interleukin 2) • IL10 (Interleukin 10) • CD40 (CD40 Molecule) • IL4 (Interleukin 4) • ITGAX (Integrin Subunit Alpha X) • CD86 (CD86 Molecule)
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nibrozetone (RRx-001)
5ms
Environmentally responsive hydrogel promotes vascular normalization to enhance STING anti-tumor immunity. (PubMed, J Control Release)
Our pre-basic found excellent anti-tumor effects of c-di-AMP and RRx-001, respectively, and we further explored whether they could be combined synergistically for anti-tumor immunotherapy...Moreover, the combination of the two presented more powerful pro-vascular normalization and reversed tumor immunosuppression than the drug alone. This study demonstrates a new design option for anti-tumor combination therapy and the potential of tumor environmentally responsive hydrogel scaffolds in combination with anti-tumor immunotherapy.
Journal
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STING (stimulator of interferon response cGAMP interactor 1)
|
nibrozetone (RRx-001)
7ms
Enrollment open • Metastases
|
cisplatin • nibrozetone (RRx-001)
8ms
Enrollment open
|
cisplatin • carboplatin • etoposide IV • nibrozetone (RRx-001)
8ms
Trial completion date
|
cisplatin • carboplatin • etoposide IV • nibrozetone (RRx-001)
8ms
PIRATE: RRx-001 Given With Irinotecan and Temozolomide for Pediatric Patients With Recurrent or Progressive Malignant Solid and Central Nervous System Tumors (clinicaltrials.gov)
P1, N=24, Active, not recruiting, EpicentRx, Inc. | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024
Trial completion date • Trial primary completion date • Combination therapy
|
temozolomide • irinotecan • nibrozetone (RRx-001)
8ms
An "All-in-one" Immunomodulator-Engineered Clinical Translatable Immunotherapy of Advanced Hepatocellular Carcinoma. (PubMed, Adv Healthc Mater)
The use of RRx-001 with the function of downregulating the expression of innate immune checkpoint molecule CD47 provides a powerful means for treating advanced HCC containing a substantial proportion of immunosuppressive macrophages...Combined with the ROS generation and an upregulated "eat me" signal level of DOX, BEA-D@R collectively increased RNS generation, enhanced T cell infiltration, and maximized macrophage phagocytosis, leading to an average of 40% tumor elimination in a mice model bearing an initial tumor of approximately 300 mm3 that mimics advanced HCC. Overall, this study uncovered the "all-in-one" immunotherapeutic functionalities of a clinical translatable nanoplatform for enhanced immunotherapy of advanced HCC.
Journal • PD(L)-1 Biomarker • IO biomarker • Immunomodulating • Metastases
|
PD-L1 (Programmed death ligand 1) • CD47 (CD47 Molecule)
|
CD47 expression
|
nibrozetone (RRx-001)
9ms
Trial initiation date • Metastases
|
cisplatin • nibrozetone (RRx-001)
12ms
Nanomedicine-based co-delivery of a calcium channel inhibitor and a small molecule targeting CD47 for lung cancer immunotherapy. (PubMed, Nat Commun)
Simultaneously, RRX-001 reduces CD47 protein levels, aiding in preventing immune escape by calreticulin-rich cancer cells. In lung tumor models in male mice, this combined approach shows anti-tumor effects and immunity against tumor re-exposure, highlighting its potential for lung cancer immunotherapy.
Journal
|
CD47 (CD47 Molecule) • CALR (Calreticulin)
|
nibrozetone (RRx-001)
1year
RRx-001 potentially reduces financial toxicity for patients and caregivers in head and neck cancer. (ASCO-QC 2023)
PREVLAR was a Phase 2 study that randomized 53 head and neck cancer patients 1:1 to receive four doses of RRx-001 prior to the start of intensity modulated radiation therapy (IMRT) in 2.0-2.2 Gy fractions/weekday to a cumulative radiation dose of up to 72 Gy plus cisplatin administered either weekly (40 mg/m2) or tri-weekly (100 mg/m2) vs. cisplatin plus IMRT alone (control). The RRx-001 “four before and no more” pre-treatment dosing regimen is not only convenient for patients and their caregivers but also reduces several toxicities including, most likely, financial toxicity. This is likely to bolster its adoption once RRx-001 becomes part of the medical armamentarium for the treatment of SOM. We plan more rigorously to test the effect of RRx-001 on financial toxicity in an upcoming Phase 2b trial in head and neck cancer called KEVLARx, n = 216.
Clinical
|
cisplatin • nibrozetone (RRx-001)
1year
Secondary Analysis of RRx-001 on the Incidence of Related Toxicities in Patients Treated with Concomitant Chemoradiation for Locally Advanced Head and Neck Cancer. (PubMed, Int J Radiat Oncol Biol Phys)
In this small proof of concept trial, RRx-001 infusion resulted in a reduction of multiple, biologically-related, side effects associated with a standard chemoradiation regimen used to the treatment of head and neck cancers. KEVLAR, a larger Phase 2b trial is planned to begin enrollment in Q4 of 2023 at about thirty sites in North America.
Journal • Metastases
|
NLRP3 (NLR Family Pyrin Domain Containing 3)
|
cisplatin • dexamethasone • nibrozetone (RRx-001)
1year
Data Management 101 for Drug Developers: A Peek Behind the Curtain. (PubMed, Clin Transl Sci)
For added color and context, the review includes real-world examples with RRx-001, a new molecular entity (NME) in Phase 3 and with fast-track status in head and neck cancer, and AdAPT-001, an oncolytic adenovirus armed with a transforming growth factor-beta (TGF-β) trap in a Phase 1/2 clinical trial with which the authors, as employees of the biopharmaceutical company, EpicentRx, are closely involved. An alphabetized glossary of key terms and acronyms used throughout this manuscript is also included for easy reference (See Table 1).
Journal
|
TGFB1 (Transforming Growth Factor Beta 1)
|
nibrozetone (RRx-001) • AIM-001
over1year
A multicenter, phase 1, dose escalation clinical trial (G-FORCE-1) of XRT, RRx-001 and temozolomide followed by temozolomide +/- RRx-001 in newly diagnosed glioblastoma. (PubMed, Front Oncol)
The overall response rate was 18.8% (3 PR out of 16) and the disease control rate was 68.8% (3 PR, 8 SD out of 16). The addition of RRx-001 to TMZ and RT and to TMZ during maintenance was safe and well-tolerated and deserves further study.
P1 data • Journal
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NLRP3 (NLR Family Pyrin Domain Containing 3)
|
temozolomide • nibrozetone (RRx-001)
over1year
RRx-001: a chimeric triple action NLRP3 inhibitor, Nrf2 inducer, and nitric oxide superagonist. (PubMed, Front Oncol)
However, unlike ADCs, whose large size impacts their pharmacokinetic properties, RRx-001 is a nonpolar small molecule that easily crosses cell membranes and the blood brain barrier (BBB) and distributes systemically. This short review is organized around the de novo design and in vivo pro-oxidant/pro-inflammatory and antioxidant/anti-inflammatory activity of RRx-001, which, in turn, depends on the reduced to oxidized glutathione ratio and the oxygenation status of tissues.
Review • Journal
|
NLRP3 (NLR Family Pyrin Domain Containing 3)
|
nibrozetone (RRx-001)
over1year
Lineage tracing of mutant granulosa cells reveals in vivo protective mechanisms that prevent granulosa cell tumorigenesis. (PubMed, Cell Death Differ)
Therefore, treatment with the Cd47 inhibitor RRX-001 was tested and found to efficiently suppress the growth of GCTs in vivo. Together, our study has revealed an immune evasion mechanism via CD24/CD47 upregulation to GCT formation, shedding light on the future potential clinical therapies for GCTs.
Preclinical • Journal
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PTEN (Phosphatase and tensin homolog) • CD24 (CD24 Molecule)
|
nibrozetone (RRx-001)
over1year
A Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation. (PubMed, Drugs)
This review discusses the current status, known mechanisms of action, and disease-modifying therapeutic potential of RRx-001, a direct NLRP3 inflammasome inhibitor under investigation in several late-stage anticancer clinical trials, including a phase 3 trial for the treatment of third-line and beyond small cell lung cancer (SCLC), an indication with no treatment, in which RRx-001 is combined with reintroduced chemotherapy from the first line, carboplatin/cisplatin and etoposide (ClinicalTrials.gov Identifier: NCT03699956). Studies from multiple independent groups have now confirmed that RRx-001 is safe and well tolerated in humans. Additionally, emerging evidence in preclinical animal models suggests that RRx-001 could be effective in a wide range of diseases where immune and inflammasome activation drives disease pathology.
Review • Journal
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IL18 (Interleukin 18) • NLRP3 (NLR Family Pyrin Domain Containing 3)
|
cisplatin • carboplatin • etoposide IV • nibrozetone (RRx-001)
over1year
Phase 1 pilot study of RRx-001 + nivolumab in patients with advanced metastatic cancer (PRIMETIME). (PubMed, Front Immunol)
Further clinical trials with RRx-001 and nivolumab are warranted. ClinicalTrials.gov identifier, NCT02518958.
P1 data • Clinical Trial,Phase I • Journal • Metastases
|
NLRP3 (NLR Family Pyrin Domain Containing 3)
|
Opdivo (nivolumab) • nibrozetone (RRx-001)
over1year
A nanodrug combining CD47 and sonodynamic therapy efficiently inhibits osteosarcoma deterioration. (PubMed, J Control Release)
In this work, for the first time, a biomimetic nanodrug named MPIRx was deveploped by loading IR780 (a sonosensitizer) and RRx-001 (a CD47 inhibitor) in PEG-PCL nanomicelles and then coating with OS cell membranes...Ultimately, MPIRx showed good tumor accumulation in vivo and successfully inhibited subcutaneous OS and orthotopic tumor with deterioration of pulmonary metastasis. Overall, by creating a local oxidative microenvironment and modulating the TAMs/CD47 in tumor tissue, the MPIRx nanodrug presents a novel strategy for macrophage-related immunotherapy to successfully eliminate OS and inhibit the intractable pulmonary metastasis.
Journal • IO biomarker
|
CD47 (CD47 Molecule)
|
CD47 overexpression
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nibrozetone (RRx-001)
almost2years
ROCKET: Phase II Randomized, Active-controlled, Multicenter Trial to Assess the Safety and Efficacy of RRx-001 + Irinotecan vs. Single-agent Regorafenib in Third/Fourth Line Colorectal Cancer. (PubMed, Clin Colorectal Cancer)
The results of this trial demonstrate improved efficacy of RxI compared with RegI in patients with metastatic colorectal cancer after previous treatment with irinotecan, and late-stage clinical development in this indication is planned on the strength of the observed "signal" accompanied by a sufficient safety profile.
P2 data • Journal
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation
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Stivarga (regorafenib) • irinotecan • nibrozetone (RRx-001)
2years
RRx-001 and the "Right stuff": Protection and treatment in outer space. (PubMed, Life Sci Space Res (Amst))
From antibiotics to aspirin to antimalarials and to anticancer agents, about half of the world's best-selling drugs are derived from nature. As manned missions to the Moon, Mars, and asteroids as well as space tourism beckon, it is perhaps fitting that a compound like RRx-001, which is derived from 1,3,3-Trinitroazetidine (TNAZ), an explosive propellant for rockets, is a potential "all purpose" option to mitigate the major biomedical effects of space radiation exposures including cancer development and other tissue degenerations both within mission and after mission. This article highlights the promise of RRx-001 to attenuate the acute and late effects of radiation exposure on astronauts including the development of cancer.
Journal
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NLRC5 (NLR Family CARD Domain Containing 5) • NLRP3 (NLR Family Pyrin Domain Containing 3)
|
nibrozetone (RRx-001) • aspirin
2years
RRx-001 in Lung Cancer, Ovarian Cancer and Neuroendocrine Tumors Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT) (clinicaltrials.gov)
P2, N=139, Completed, EpicentRx, Inc. | Active, not recruiting --> Completed | N=213 --> 139 | Trial completion date: Jan 2023 --> Dec 2021 | Trial primary completion date: Jan 2023 --> Dec 2021
Trial completion • Enrollment change • Trial completion date • Trial primary completion date
|
EGFR (Epidermal growth factor receptor)
|
EGFR mutation
|
cisplatin • carboplatin • gemcitabine • albumin-bound paclitaxel • pemetrexed • etoposide IV • irinotecan • pegylated liposomal doxorubicin • vinorelbine tartrate • nibrozetone (RRx-001)
2years
Natural and synthetic compounds in Ovarian Cancer: A focus on NRF2/KEAP1 pathway. (PubMed, Pharmacol Res)
In this review we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 (Kelch Like ECH Associated Protein 1) pathway in in vitro models of ovarian cancer. In particular, we reported how these compounds can modulate chemotherapy response.
Review • Journal
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KEAP1 (Kelch Like ECH Associated Protein 1) • CAT (Catalase)
|
cisplatin • AiTan (rivoceranib) • erastin • nibrozetone (RRx-001)
over2years
Interference With Redox Homeostasis Through a G6PD-Targeting Self-Assembled Hydrogel for the Enhancement of Sonodynamic Therapy in Breast Cancer. (PubMed, Front Chem)
Herein, in this study, with G6PD, the gatekeeper enzyme of the pentose phosphate pathway, as the regulative target, a self-assembled thermosensitive chitosan-pluronic hydrogel coloaded with ICG (sono-sensitive agent) and RRx-001 (IR@CPGel) was successfully prepared to enhance SDT through interference with redox homeostasis...Taken together, this work aimed to enhance the efficacy of sonodynamic therapy through local administration of self-assembled IR@CPGel to interfere with redox homeostasis and thus amplify the oxidative stress microenvironment in tumor tissues. In a word, this work provides a new strategy for the SDT enhancement in breast cancer therapy.
Journal
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HIF1A (Hypoxia inducible factor 1, alpha subunit) • MMP2 (Matrix metallopeptidase 2) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • G6PD (Glucose-6-Phosphate Dehydrogenase) • ZEB1 (Zinc Finger E-box Binding Homeobox 1)
|
HIF1A expression
|
nibrozetone (RRx-001)
over2years
Trial completion
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS wild-type • RAS wild-type
|
Avastin (bevacizumab) • Stivarga (regorafenib) • irinotecan • nibrozetone (RRx-001)
over2years
RRx-001 in Lung Cancer, Ovarian Cancer and Neuroendocrine Tumors Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT) (clinicaltrials.gov)
P2, N=213, Active, not recruiting, EpicentRx, Inc. | Trial completion date: Jun 2022 --> Jan 2023 | Trial primary completion date: Dec 2021 --> Jan 2023
Trial completion date • Trial primary completion date
|
EGFR (Epidermal growth factor receptor)
|
EGFR mutation
|
cisplatin • carboplatin • gemcitabine • albumin-bound paclitaxel • pemetrexed • etoposide IV • irinotecan • pegylated liposomal doxorubicin • vinorelbine tartrate • nibrozetone (RRx-001)
over2years
The small molecule NLRP3 inhibitor RRx-001 potentiates regorafenib activity and attenuates regorafenib-induced toxicity in mice bearing human colorectal cancer xenografts. (PubMed, Am J Cancer Res)
RRx-001 demonstrated in vitro and in vivo synergy with regorafenib with attenuation of toxicity in colorectal cancer cell lines. These results provide a rationale to treat colorectal cancer with RRx-001 plus another tyrosine kinase inhibitor like regorafenib.
Preclinical • Journal
|
NLRP3 (NLR Family Pyrin Domain Containing 3)
|
Stivarga (regorafenib) • nibrozetone (RRx-001)
over2years
BRD4 Targets the KEAP1-Nrf2-G6PD Axis and Suppresses Redox Metabolism in Small Cell Lung Cancer. (PubMed, Antioxidants (Basel))
Furthermore, simultaneous application of JQ1 and ATRA or RRx-001 yielded synergistic inhibition both in vitro and in vivo. These data suggest metabolic reprogramming by JQ1 treatment improves cell resistance to oxidative stress and might be a resistance mechanism to bromodomain and extra-terminal domain (BET) inhibition therapy. Altogether, our findings provide novel insight into the transcriptional regulatory network of BRD4 and KEAP1 and transcriptional regulation of the pentose phosphate pathway in SCLC.
Journal
|
KEAP1 (Kelch Like ECH Associated Protein 1) • BRD4 (Bromodomain Containing 4)
|
JQ-1 • nibrozetone (RRx-001)
almost3years
Long noncoding RNA Linc00173 modulates glucose metabolism and multidrug chemoresistance in small cell lung cancer: Potential molecular panel for targeted therapy. (PubMed, Mol Ther)
Furthermore, we demonstrated that the inhibitors of HK2 and G6PD, 3-BrPA and RRx-001, exhibit a synergistic anti-tumor effect with chemotherapy both in vitro and in vivo including a PDX model. For the first time, we identified the mechanism of Linc00173/YB1 axis induced glucose metabolic rewiring in SCLC, indicating that glucose metabolic enzymes HK2 and G6PD may be potential therapeutic targets for SCLC treatments.
Journal
|
YBX1 (Y-Box Binding Protein 1)
|
nibrozetone (RRx-001)
3years
RRx-001 in Lung Cancer, Ovarian Cancer and Neuroendocrine Tumors Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT) (clinicaltrials.gov)
P2, N=213, Active, not recruiting, EpicentRx, Inc. | Trial completion date: Jun 2021 --> Jun 2022 | Trial primary completion date: Dec 2020 --> Dec 2021
Trial completion date • Trial primary completion date
|
EGFR (Epidermal growth factor receptor)
|
EGFR mutation
|
cisplatin • carboplatin • gemcitabine • albumin-bound paclitaxel • pemetrexed • etoposide IV • irinotecan • pegylated liposomal doxorubicin • vinorelbine tartrate • nibrozetone (RRx-001)
over3years
Discovery of RRx-001, a Myc and CD47 Downregulating Small Molecule with Tumor Targeted Cytotoxicity and Healthy Tissue Cytoprotective Properties in Clinical Development. (PubMed, J Med Chem)
The question of exactly how RRx-001 does this, and by means of what mechanism(s), depending on the route of delivery, intravenous or intratumoral, are explored. RRx-001 is currently in phase 2 and 3 clinical trials for the treatment of multiple solid tumor malignancies and as a supportive care drug.
Clinical • Journal
|
CD47 (CD47 Molecule)
|
nibrozetone (RRx-001)
almost4years
In small cell lung cancer patients treated with RRx-001, a downregulator of CD47, decreased expression of PD-L1 on circulating tumor cells significantly correlates with clinical benefit. (PubMed, Transl Lung Cancer Res)
P2, These results suggest that PD-L1 expression on CTCs decreased after RRx-001 was significantly correlated with response to reintroduced platinum-based doublet therapy. Monitoring PD-L1 expression on CTCs during RRx-001 treatment may serve as a biomarker to predict response to RRx-001-based cancer therapy.
Clinical • Journal • Circulating Tumor Cells • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD47 (CD47 Molecule)
|
PD-L1 expression
|
nibrozetone (RRx-001)
over4years
ROCKET: A Phase 2 Randomized, Open-Label Study of RRx-001 vs Regorafenib in Subjects With Metastatic Colorectal Cancer (clinicaltrials.gov)
P2, N=57, Active, not recruiting, EpicentRx, Inc. | Trial completion date: Jun 2020 --> Dec 2020 | Trial primary completion date: Jun 2020 --> Dec 2020
Clinical • Trial completion date • Trial primary completion date
|
KRAS (KRAS proto-oncogene GTPase)
|
Avastin (bevacizumab) • Stivarga (regorafenib) • irinotecan • nibrozetone (RRx-001)
over4years
[VIRTUAL] Correlation of decreased expression of PD-L1 on circulating tumor cells and clinical benefit in SCLC Patients treated with RRx-001, a CD47 downregulator, in a phase II trial. (ASCO 2020)
Reduction of PD-L1 expression was correlated with good clinical outcome after RRx-001 + platinum doublet treatment. PD-L1 expression reduction in favor of RRx-001 RECIST clinical benefit was clinically significant as compared to non-responders with progressive disease (PD). In the ongoing SCLC Phase 3 study called REPLATINUM (NCT03699956), analyses are planned to correlate response and survival with expression of CD47 and PD-L1 on CTCs.
Clinical • P2 data • Circulating Tumor Cells • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • EPCAM (Epithelial cell adhesion molecule)
|
PD-L1 expression
|
nibrozetone (RRx-001)
over4years
[VIRTUAL] A phase III trial-in-progress called REPLATINUM that compares RRx-001 + a platinum doublet to a platinum doublet in third-line or beyond small cell lung cancer. (ASCO 2020)
This US-based, open-label, randomized, phase 3 study (NCT03777657) compares RRx-001 4mg + a platinum doublet (carboplatin or cisplatin + etoposide) versus a platinum doublet for pts with 3rd line or beyond SCLC that have previously received a checkpoint inhibitor. Exploratory endpoints include c-Myc, CD-47 and PD-L1 on circulating tumor cells and SIRP-alpha expression on circulating monocytes. Research Funding: EpicentRx
P3 data • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • MYC (V-myc avian myelocytomatosis viral oncogene homolog)
|
cisplatin • carboplatin • etoposide IV • nibrozetone (RRx-001)