RBS2418 for Cancer

Recruiting in Palo Alto (17 mi)

+18 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Riboscience, LLC.

Must not be taking: Immunomodulators, Immunosuppressants

Disqualifiers: Rapid progression, Uncontrolled pain, Autoimmune, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called RBS2418, alone or with pembrolizumab, for patients with advanced tumors who haven't responded to other treatments. The drug works by boosting the body's natural defenses to better recognize and destroy cancer cells.

Will I have to stop taking my current medications?

The trial requires that you stop any approved anti-cancer therapy, including chemotherapy, targeted small molecule therapy, or radiation therapy, at least 2 weeks before starting the trial. Additionally, you must not have taken systemic immunomodulating agents within 4 weeks or systemic immunosuppressive medication within 2 weeks prior to the trial.

What makes the drug RBS2418 unique for cancer treatment?

RBS2418 is unique because it targets the ENPP1 enzyme, which is involved in insulin signaling and glucose metabolism, potentially offering a novel approach to cancer treatment by affecting cellular processes differently than traditional therapies.

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Eligibility Criteria

Adults with advanced, inoperable or metastatic tumors who've tried all standard treatments without success can join. They must have a life expectancy of at least 3 months, be able to perform daily activities (with some limitations), and provide consent. Pregnant women are excluded, as well as those with severe allergies to certain drugs or uncontrolled cancer symptoms.

Inclusion Criteria

Have histologically or cytologically confirmed cancer diagnosis based on pathology report

My blood, kidney, liver, and clotting tests are all within normal ranges.

I can care for myself and am up and about more than 50% of my waking hours.

Exclusion Criteria

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

I am on treatment for active HIV or my HIV is not under control.

I haven't taken any immune system affecting drugs in the last 4 weeks or before.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

Up to 4 weeks

1 visit (in-person)

Dose Escalation

Participants receive ascending doses of RBS2418 as monotherapy or in combination with pembrolizumab to identify the fixed dose for the expansion phase

Variable, up to 2 years

Visits every 3 weeks

Expansion

Participants receive a fixed dose of RBS2418 as determined by the dose escalation phase

Variable, up to 2 years

Visits every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days for AE monitoring, 90 days for SAE monitoring

1 visit (in-person)

Participant Groups

RBS2418 is being tested for its ability to boost the body's immune response against tumors by affecting cellular compounds like cGAMP and ATP. This trial will explore RBS2418 alone or combined with pembrolizumab in patients whose cancers haven't responded to standard care.

Group I: Treatment Group B Experimental Treatment 1 Intervention

After dose escalation phase is completed in both monotherapy and combination therapy setting (A-1 and A-2), an expansion treatment group will be enrolled, and subjects (n=20- 40) will be treated with a fixed dose of RBS2418 to be selected by the Sponsor in consultation with the SRC and after reviewing the totality of the dose escalation data both as monotherapy and combination therapy.

Group II: Treatment Group A-2 Experimental Treatment 1 Intervention

For Treatment Group A-2, a cohort of three (3) subjects will be dosed at the starting dose of 100 mg twice a day (BID) of RBS2418 in combination with pembrolizumab 200 mg IV (administered on Day 1 and every 3 weeks). Subsequent subjects will then be enrolled in serial, three (3) subject cohorts, with 100% dose increments (doubling the dose) until 800 mg BID

Group III: Treatment Group A-1 Experimental Treatment 1 Intervention

For Treatment Group A-1, a cohort of three (3) subjects will be dosed at the starting dose of 100 mg twice a day (BID) of RBS2418. Subsequent subjects will then be enrolled in serial, three (3) subject cohorts, with 100% dose increments (doubling the dose) until 800 mg BID

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Baltimore, MD

Jordan Berlin, MD Nashville, TN

Norton Cancer Louisville, KY

Ochsner MD Anderson Cancer Center New Orleans, LA

More Trial Locations

Who Is Running the Clinical Trial?

Riboscience, LLC. Lead Sponsor

Oncobay Clinical, Inc Collaborator

References

1. England pubmed.ncbi.nlm.nih.gov

INPP4B exerts a dual function in the stemness of colorectal cancer stem-like cells through regulating Sox2 and Nanog expression. [2020] Inositol polyphosphate 4-phosphatase type II (INPP4B), a lipid phosphatase, was identified as a negative regulator of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in several cancers. The expression and biological function of INPP4B in human colorectal cancer (CRC) are controversial, while the role and molecular mechanism of INPP4B in colorectal cancer stem-like cells (CR-CSLCs) remains unclear. Here, we observed that INPP4B expression was markedly decreased in primary non-metastatic CR-CSLCs and increased in highly metastatic CR-CSLCs compared with corresponding control non-CSLCs. INPP4B overexpression inhibited self-renewal, and chemoresistance of primary non-metastatic CR-CSLCs, but exerted the opposite roles in highly metastatic CR-CSLCs in vitro. Similarly, INPP4B knockdown had dual functions in the self-renewal and chemoresistance of different CR-CSLCs. In addition, we demonstrated that INPP4B overexpression suppressed the tumorigenicity of primary non-metastatic CR-CSLCs while induced the tumorigenicity of highly metastatic CR-CSLCs in nude mice. Furthermore, INPP4B was found to modulate the stemness of CR-CSLCs by regulating Sox2 and Nanog expression, which was dependent on PI3K/PTEN/Akt signaling. In conclusion, our results highlight an important role of INPP4B in the stemness of CR-CSLCs for the first time and emphasize INPP4B as a dual therapeutic target for suppressing primary cancer cell proliferation and for preventing metastasis in CRC patients.

2. Germany pubmed.ncbi.nlm.nih.gov

The ENPP1 K121Q polymorphism determines individual susceptibility to the insulin-sensitising effect of lifestyle intervention. [2021] The K121Q (rs1044498) single nucleotide polymorphism (SNP) in the ENPP1 gene has shown association with insulin resistance and type 2 diabetes in various ethnic populations. We hypothesised that K121Q may predict the success of lifestyle intervention in terms of improvement of insulin sensitivity.

3. United States pubmed.ncbi.nlm.nih.gov

SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer. [2022] Oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), occur with high frequency in breast cancer. The protein kinase Akt is considered to be the primary effector of PIK3CA, although mechanisms by which PI3K mediates Akt-independent tumorigenic signals remain obscure. We show that serum and glucocorticoid-regulated kinase 3 (SGK3) is amplified in breast cancer and activated downstream of PIK3CA in a manner dependent on the phosphoinositide phosphatase INPP4B. Expression of INPP4B leads to enhanced SGK3 activation and suppression of Akt phosphorylation. Activation of SGK3 downstream of PIK3CA and INPP4B is required for 3D proliferation, invasive migration, and tumorigenesis in vivo. We further show that SGK3 targets the metastasis suppressor NDRG1 for degradation by Fbw7. We propose a model in which breast cancers harboring oncogenic PIK3CA activate SGK3 signaling while suppressing Akt, indicative of oncogenic functions for both INPP4B and SGK3 in these tumors.

4. United States pubmed.ncbi.nlm.nih.gov

In Vivo Role of INPP4B in Tumor and Metastasis Suppression through Regulation of PI3K-AKT Signaling at Endosomes. [2018] The phosphatases PTEN and INPP4B have been proposed to act as tumor suppressors by antagonizing PI3K-AKT signaling and are frequently dysregulated in human cancer. Although PTEN has been extensively studied, little is known about the underlying mechanisms by which INPP4B exerts its tumor-suppressive function and its role in tumorigenesis in vivo. Here, we show that a partial or complete loss of Inpp4b morphs benign thyroid adenoma lesions in Pten heterozygous mice into lethal and metastatic follicular-like thyroid cancer (FTC). Importantly, analyses of human thyroid cancer cell lines and specimens reveal INPP4B downregulation in FTC. Mechanistically, we find that INPP4B, but not PTEN, is enriched in the early endosomes of thyroid cancer cells, where it selectively inhibits AKT2 activation and in turn tumor proliferation and anchorage-independent growth. We therefore identify INPP4B as a novel tumor suppressor in FTC oncogenesis and metastasis through localized regulation of the PI3K-AKT pathway at the endosomes.

5. United States pubmed.ncbi.nlm.nih.gov

ENPP1 affects insulin action and secretion: evidences from in vitro studies. [2021] The aim of this study was to deeper investigate the mechanisms through which ENPP1, a negative modulator of insulin receptor (IR) activation, plays a role on insulin signaling, insulin secretion and eventually glucose metabolism. ENPP1 cDNA (carrying either K121 or Q121 variant) was transfected in HepG2 liver-, L6 skeletal muscle- and INS1E beta-cells. Insulin-induced IR-autophosphorylation (HepG2, L6, INS1E), Akt-Ser(473), ERK1/2-Thr(202)/Tyr(204) and GSK3-beta Ser(9) phosphorylation (HepG2, L6), PEPCK mRNA levels (HepG2) and 2-deoxy-D-glucose uptake (L6) was studied. GLUT 4 mRNA (L6), insulin secretion and caspase-3 activation (INS1E) were also investigated. Insulin-induced IR-autophosphorylation was decreased in HepG2-K, L6-K, INS1E-K (20%, 52% and 11% reduction vs. untransfected cells) and twice as much in HepG2-Q, L6-Q, INS1E-Q (44%, 92% and 30%). Similar data were obtained with Akt-Ser(473), ERK1/2-Thr(202)/Tyr(204) and GSK3-beta Ser(9) in HepG2 and L6. Insulin-induced reduction of PEPCK mRNA was progressively lower in untransfected, HepG2-K and HepG2-Q cells (65%, 54%, 23%). Insulin-induced glucose uptake in untransfected L6 (60% increase over basal), was totally abolished in L6-K and L6-Q cells. GLUT 4 mRNA was slightly reduced in L6-K and twice as much in L6-Q (13% and 25% reduction vs. untransfected cells). Glucose-induced insulin secretion was 60% reduced in INS1E-K and almost abolished in INS1E-Q. Serum deficiency activated caspase-3 by two, three and four folds in untransfected INS1E, INS1E-K and INS1E-Q. Glyburide-induced insulin secretion was reduced by 50% in isolated human islets from homozygous QQ donors as compared to those from KK and KQ individuals. Our data clearly indicate that ENPP1, especially when the Q121 variant is operating, affects insulin signaling and glucose metabolism in skeletal muscle- and liver-cells and both function and survival of insulin secreting beta-cells, thus representing a strong pathogenic factor predisposing to insulin resistance, defective insulin secretion and glucose metabolism abnormalities.