REM-422 for Advanced Cancer
Recruiting in Palo Alto (17 mi)
+5 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Remix Therapeutics
Must not be taking: CYP3A inhibitors, CYP3A inducers, Antacids
Disqualifiers: Active infection, HIV, Hepatitis, others
No Placebo Group
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?This trial is testing REM-422, an oral medicine, in people with advanced Adenoid Cystic Carcinoma (ACC) that has returned or spread. REM-422 aims to reduce a protein needed for cancer growth by breaking down its mRNA. The study will determine the best dose and evaluate its safety and effectiveness.
Will I have to stop taking my current medications?
The trial requires that participants stop using certain medications, such as strong CYP3A inhibitors or inducers, drugs that reduce stomach acid, and any prohibited medication at least 1 week before starting REM-422. If you are on these medications, you may need to stop or adjust them before joining the trial.
What data supports the effectiveness of the drug REM-422 for advanced cancer?
Research shows that targeting the MYB gene, which REM-422 aims to degrade, can reduce cancer cell growth in various cancers like acute myeloid leukemia and adenoid cystic carcinoma. Similar treatments that inhibit MYB have shown promise in reducing cancer cell viability and proliferation.
12345What makes the drug REM-422 unique for treating advanced cancer?
REM-422 is unique because it specifically targets and degrades the MYB mRNA, a key factor in the growth of certain cancers, which is a novel approach compared to traditional treatments that may not directly target this transcription factor.
12467Eligibility Criteria
Adults with advanced Adenoid Cystic Carcinoma (ACC) who can consent, swallow pills, and have proper organ function. They must not have had recent non-study cancer treatments or major surgeries and should show disease progression. Women of childbearing age must test negative for pregnancy and agree to contraception.Inclusion Criteria
Be able to provide informed consent.
My cancer is advanced or has spread to other parts of my body.
My cancer has worsened or I have symptoms like pain or trouble breathing, and I haven't tolerated other treatments well.
+13 more
Exclusion Criteria
Participants receiving any other investigational treatment for any indication ≤ 3 weeks prior to enrollment.
Unwillingness or inability to follow protocol requirements.
I need or will need daily corticosteroid treatment equivalent to 10 mg of prednisone or more.
+18 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Participants receive escalating doses of REM-422 to determine Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D)
Until MTD/RP2D is determined
Dose Expansion
Participants receive REM-422 at the identified RP2D to further evaluate safety and anti-tumor activity
Until disease progression, therapy intolerance, or participant withdrawal
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Safety evaluation will continue until 30 days after last administration of REM-422
Participant Groups
The study tests REM-422's safety and effectiveness against ACC tumors. Participants will take this MYB mRNA degrader orally, with the trial having two phases: dose escalation for those showing symptoms or stable disease on intolerable treatment, and dose expansion for measurable progressing disease.
1Treatment groups
Experimental Treatment
Group I: REM-422Experimental Treatment1 Intervention
* Dose Escalation: Participants will receive escalating doses of REM-422 to determine Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D)-422, oral capsule administered once daily
* Dose Expansion: Participants will receive REM-422 at the identified RP2D
* Treatment will continue until disease progression, therapy intolerance, or participant withdrawal
* Safety evaluation will continue until 30 days of last administration of REM-422
REM-422 is already approved in United States for the following indications:
🇺🇸 Approved in United States as REM-422 for:
- Adenoid Cystic Carcinoma (ACC)
- Acute Myeloid Leukemia (AML)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of California San Francisco Helen Diller Comprehensive Cancer CenterSan Francisco, CA
MD Anderson Cancer CenterHouston, TX
Sarah Cannon Research InstituteNashville, TN
Memorial Sloan Kettering Cancer CenterNew York, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Remix TherapeuticsLead Sponsor
References
Proteasome inhibitors suppress MYB oncogenic activity in a p300-dependent manner. [2022]Studies of the role of MYB in human malignancies have highlighted MYB as a potential drug target for acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Although transcription factors are often considered un-druggable, recent work has demonstrated successful targeting of MYB by low molecular weight compounds. This has fueled the notion that inhibition of MYB has potential as a therapeutic approach against MYB-driven malignancies. Here, we have used a MYB reporter cell line to screen a library of FDA-approved drugs for novel MYB inhibitors. We demonstrate that proteasome inhibitors have significant MYB-inhibitory activity, prompting us to characterize the proteasome inhibitor oprozomib in more detail. Oprozomib was shown to interfere with the ability of the co-activator p300 to stimulate MYB activity and to exert anti-proliferative effects on human AML and ACC cells. Overall, our work demonstrated suppression of oncogenic MYB activity as a novel result of proteasome inhibition.
Inhibition of proliferation by c-myb antisense oligodeoxynucleotides in colon adenocarcinoma cell lines that express c-myb. [2013]Steady-state mRNA levels of the protooncogene c-myb were measured by Northern blot analysis in the human colon carcinoma cell lines LoVo, the doxorubicin-resistant derivative LoVo/Dx, Colo 205, and HT 29. Overexpression of c-myb mRNA was detected in the Colo 205 cell line, probably because of gene amplification, while in human HT 29 cells c-myb was not expressed at a detectable level. Comparison between LoVo and LoVo/Dx cell lines showed that c-myb mRNA levels were much higher in the doxorubicin-resistant derivative than in the parental line. c-myb antisense oligodeoxynucleotides inhibited cell proliferation only in the cell lines with detectable mRNA c-myb (LoVo, LoVo/DX, and Colo 205). The dose of antisense exerting inhibitory effect was related to the levels of c-myb mRNA expression. Inhibition of c-myb expression in antisense-treated LoVo/DX cells was demonstrated by the reverse transcriptase polymerase chain reaction technique. LoVo/Dx cells were induced to differentiate by treatment with dimethylformamide to determine whether down-regulation of c-myb expression would accompany the process of differentiation. During the treatment with dimethylformamide the expression of c-myb decreased in parallel with the reduction of cell growth, while terminal differentiation of these cells was associated with changes in the expression of carcinoembryonic antigen and laminin receptor genes. Our findings demonstrate that the expression of c-myb is important for the proliferation of colon carcinoma cell lines and suggest that the role of this protooncogene is not restricted to cells of hematopoietic origin but is more general than previously thought.
Normal and leukemic hematopoietic cells manifest differential sensitivity to inhibitory effects of c-myb antisense oligodeoxynucleotides: an in vitro study relevant to bone marrow purging. [2022]The c-myb protooncogene is preferentially expressed in hematopoietic cells, and its encoded protein, Myb, is required for hematopoietic cell proliferation. To analyze the relative Myb dependence of normal and leukemic human hematopoietic progenitor cells, normal bone marrow cells, several types of leukemic blast cells, and 1:1 mixtures of normal and leukemic cells were cultured in the presence of c-myb sense or antisense oligodeoxynucleotides; cell viability and cloning efficiency were then assessed. c-myb sense oligomers had negligible effects on normal and leukemic cells. In contrast, c-myb antisense oligomers strongly inhibited or completely abolished clonogenic growth of a T-cell leukemia line, 78% (18 of 23) of primary acute myelogenous leukemia cases examined, and 4 of 5 primary chronic myelogenous leukemia (CML) cases in blast crisis. In three of the latter patients, polymerase chain reaction analysis of a 1:1 mixture of c-myb antisense-treated normal and CML cells revealed a complete absence of bcr-abl expression, suggesting that the CML clonogenic units had been completely eliminated from the cultures. At antisense doses that inhibited leukemic cell growth, normal hematopoietic progenitor cells survived. Thus, normal and leukemic hematopoietic cells show differential sensitivity to the toxic effects of c-myb antisense DNA. Perturbation of c-myb function with antisense oligodeoxynucleotides might eventually form the basis for a molecular approach to leukemia therapy, perhaps most immediately as ex vivo bone marrow purging agents.
Bcr-TMP, a Novel Nanomolar-Active Compound That Exhibits Both MYB- and Microtubule-Inhibitory Activity. [2022]Studies of the role of MYB in human malignancies have highlighted MYB as a potential drug target for acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Here, we present the initial characterization of 2-amino-4-(3,4,5-trimethoxyphenyl)-4H-naphtho[1,2-b]pyran-3-carbonitrile (Bcr-TMP), a nanomolar-active MYB-inhibitory compound identified in a screen for novel MYB inhibitors. Bcr-TMP affects MYB function in a dual manner by inducing its degradation and suppressing its transactivation potential by disrupting its cooperation with co-activator p300. Bcr-TMP also interferes with the p300-dependent stimulation of C/EBPβ, a transcription factor co-operating with MYB in myeloid cells, indicating that Bcr-TMP is a p300-inhibitor. Bcr-TMP reduces the viability of AML cell lines at nanomolar concentrations and induces cell-death and expression of myeloid differentiation markers. It also down-regulates the expression of MYB target genes and exerts stronger anti-proliferative effects on MYB-addicted primary murine AML cells and patient-derived ACC cells than on their non-oncogenic counterparts. Surprisingly, we observed that Bcr-TMP also has microtubule-disrupting activity, pointing to a possible link between MYB-activity and microtubule stability. Overall, Bcr-TMP is a highly potent multifunctional MYB-inhibitory agent that warrants further investigation of its therapeutic potential and mechanism(s) of action.
Role of c-Myb in the survival of pre B-cell acute lymphoblastic leukemia and leukemogenesis. [2021]Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The current treatment protocol for ALL involves an intense chemotherapy regimen yielding cure rates of nearly 80%. However, new therapies need to be designed not only to increase the survival rate but also to combat the risk of severe therapy associated toxicities including secondary malignancies, growth problems, organ damage, and infertility. The c-Myb proto-oncogene is highly expressed in immature hematopoietic cells. In this study, we demonstrate that loss of c-Myb itself decreased the viability of these leukemic cells. Additionally, the inhibition of c-Myb caused a decrease in cell proliferation, significantly increased the number of cells in G(0) /G(1) phase of the cell cycle, increased the sensitivity of pre-B-ALL cells to cytotoxic agents in vitro, and significantly delayed disease onset in a mouse model of leukemia. Furthermore, we demonstrate that Bcl-2 is a target of c-Myb in pre-B-ALL cells. Our results identify c-Myb as a potential therapeutic target in pre-B-ALL and suggest that suppression of c-Myb levels or activity, in combination with currently used therapies and/or dose reduction, may lead to a decrease in toxicity and an increase in patient survival rates. Because c-Myb is aberrantly expressed in several other malignancies, targeting c-Myb will have broad clinical applications.
Reassessing the Potential of Myb-targeted Anti-cancer Therapy. [2020]Transcription factor MYB is essential for the tumorigenesis of multiple cancers, especially leukemia, breast cancer, colon cancer, adenoid cystic carcinoma and brain cancer. Thus, MYB has been regarded as an attractive target for tumor therapy. However, pioneer studies of antisense oligodeoxynucleotides against MYB, which were launched three decades ago in leukemia therapy, were discontinued because of their unsatisfactory clinical outcomes. In recent years, the roles of MYB in tumor transformation have become increasingly clear. Moreover, the regulatory mechanisms of MYB, such as the vital effects of MYB co-regulators on MYB activity and of transcriptional elongation on MYB expression, have been unveiled. These observations have underpinned novel approaches in inhibiting MYB. This review discusses the structure, function and regulation of MYB, focusing on recent insights into MYB-associated oncogenesis and how MYB-targeted therapeutics can be explored. Additionally, the main MYB-targeted therapies, including novel genetic therapy, RNA interference, microRNAs and low-molecular-weight compounds, which are especially promising inhibitors that target MYB co-regulators and transcriptional elongation, are described, and their prospects are assessed.
Effects of the antisense v-myb' expression on K562 human leukemia cell proliferation and differentiation. [2019]Recombinant plasmids containing v-myb' (803 bp fragment of the 3' end of v-myb) were constructed to induce sense or antisense v-myb' RNA expression with dexamethasone in human cells. These plasmids were used as a tool for the investigation of the role of c-myb gene in human leukemia cell proliferation and differentiation. They were transfected by electroporation into the K562 human leukemia cell line derived from a patient with chronic myelogenous leukemia in blastic crisis. After induction of transcription by dexamethasone, the plasmid with antisense v-myb' repressed the expression of p75c-myb from the endogenous c-myb gene of K562 cells. It also reduced the proliferation rate of K562 cells to 50% of the control level, and induced these K562 cells to express the myelomonocytic differentiation cell surface marker CD13 and increased NBT reducing activity. The plasmid with sense v-myb' did not have an effect on p75c-myb expression, the proliferation of K562 cells or the expression of myelomonocytic differentiation phenotypes. These observations suggest that antisense v-myb' RNA represses p75c-myb expression and that a decrease of p75c-myb suppresses K562 cell proliferation and induces its differentiation towards the myelomonocytic lineage.