RAPA-201 Immunotherapy for Solid Cancers

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Rapa Therapeutics LLC

Must be taking: Anti-PD-(L)1 antibodies

Disqualifiers: Other malignancy, HIV, Hepatitis, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment using RAPA-201 cells for patients with advanced solid tumors that have not responded to previous treatments. These reprogrammed immune cells are designed to survive better in tumors and attack cancer cells more effectively. The study aims to see if this new approach can help control tumor growth in these patients.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must be at least two weeks from your last cancer treatment, and you should have recovered from any treatment-related side effects.

What data supports the effectiveness of the RAPA-201 drug for solid cancers?

Research shows that rapamycin, a component of RAPA-201, can inhibit tumor growth and improve immune responses against cancer by affecting T-cells, which are important for fighting tumors. Additionally, rapamycin has been shown to reduce cancer risk while providing effective immunosuppression, suggesting its potential in cancer treatment. ^{1 2 3 4 5}

Is RAPA-201 immunotherapy generally safe for humans?

RAPA-201, also known as rapamycin, has been studied in various clinical trials and is generally considered safe, with some side effects like high cholesterol and low blood cell counts. In a study involving rapamycin-resistant T cells, there was no transplant-related death, and the treatment was deemed safe, although some patients experienced graft-versus-host disease (a condition where donor cells attack the recipient's body). ^{3 6 7 8 9}

How is the RAPA-201 drug different from other cancer treatments?

RAPA-201 involves using rapamycin-resistant T cells, which is unique because it aims to overcome the resistance that some cancers have to rapamycin, a drug that inhibits cell growth pathways. This approach is different from standard treatments as it specifically targets the resistance mechanism, potentially improving effectiveness in solid cancers. ^{6 10 11 12 13}

Research Team

Daniel Fowler, M.D.

Principal Investigator

Rapa Therapeutics LLC

Eligibility Criteria

This trial is for adults with advanced solid tumors that have not responded to prior treatments including anti-PD-(L)1 therapy. Participants must be in relatively good health, with a performance status of ≤ 2 and adequate organ function. They should not have central nervous system metastasis or other active cancers, and must agree to use contraception if applicable.

Inclusion Criteria

Your AST and ALT levels should be less than 3 times the upper limit of normal.

Your absolute neutrophil count is at least 1500 cells per microliter.

Your bilirubin level should be less than 1.5 mg/dL, unless you have Gilbert's disease.

Exclusion Criteria

I have HIV, hepatitis B, or C but it's under control with treatment.

Pregnant or breastfeeding patients

I have not had a heart attack in the last 6 months.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy (Cycle 1)

Administration of standard-of-care chemotherapy (carboplatin + paclitaxel) to prepare for RAPA-201 cell therapy

4 weeks

3 visits (in-person)

Treatment (Cycles 2-6)

Combination of RAPA-201 cell therapy with chemotherapy (carboplatin + paclitaxel)

20 weeks

15 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Chemotherapy Prior to RAPA-201 Therapy (Alkylating agents)
• RAPA-201 Rapamycin Resistant T Cells (CAR T-cell Therapy)

Trial Overview The study tests RAPA-201 T cell therapy combined with standard chemotherapy (carboplatin + paclitaxel). It's designed for patients whose tumors didn't respond to checkpoint inhibitor therapies. The goal is to see if this new treatment can shrink the tumors in patients who've already tried other treatments.

Participant Groups

Group I: Administration of RAPA-201 cells Experimental Treatment 2 Interventions

RAPA-201 cells will be administered at a target flat dose of 400 x 10\^6 cells per infusion.

Who Is Running the Clinical Trial?

Rapa Therapeutics LLC

Lead Sponsor

Trials

6

Recruited

200+

Findings from Research

mTOR inhibitors, while effective anti-tumor drugs, can have immunosuppressive side effects, but adjusting their dose and duration may enhance the activity of CD8+ T-cells, which are crucial for tumor immunity.

Monitoring CD8+ T-cell activity in cancer patients treated with mTOR inhibitors could help identify those who might benefit from immunotherapy, suggesting a need for personalized treatment adjustments to maximize therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring of CD8(+) T-cell Activity in mTOR Inhibitor-treated Cancer Patients for Successful Immunotherapy. Bolourian, A., Mojtahedi, Z.[2021]

Rapamycin inhibits the mTOR pathway, which plays a crucial role in regulating growth and immune responses, making it effective as both an immunosuppressant for preventing transplant rejection and as an immunostimulant that may help fight cancer.

The effectiveness of rapamycin can vary based on dosage and administration schedule, with lower doses promoting immune stimulation and intermittent dosing reducing side effects, suggesting its potential as a chemopreventive agent for low-grade cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunologic and dose dependent effects of rapamycin and its evolving role in chemoprevention. O'Shea, AE., Valdera, FA., Ensley, D., et al.[2022]

In a phase 2 clinical trial involving 40 patients with refractory hematologic malignancies, the use of rapamycin-resistant donor CD4(+) T cells (T-Rapa) after hematopoietic cell transplantation showed a low incidence of acute graft-versus-host disease (GVHD) at 20% and 40% by days 100 and 180, respectively, indicating a safer approach to treatment.

The therapy resulted in 45% of patients achieving sustained complete remission over a follow-up period of 42 to 84 months, demonstrating the efficacy of T-Rapa cells in enhancing immune reconstitution and facilitating engraftment without transplant-related mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation. Fowler, DH., Mossoba, ME., Steinberg, SM., et al.[2021]

Rapamycin (RAPA) is a new immunosuppressive drug that not only provides effective immunosuppression but also may reduce the risk of cancer development in organ transplant patients, as shown in mouse models.

Unlike cyclosporine, which promotes tumor growth, RAPA inhibits metastatic tumor growth and angiogenesis by decreasing vascular endothelial growth factor (VEGF) production, suggesting it could be a safer alternative for high-risk transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Guba, M., von Breitenbuch, P., Steinbauer, M., et al.[2022]

Rapamycin (RAPA) significantly promotes the expansion and survival of regulatory T cells (Treg) in humans, particularly enhancing the CD4(+) CD25(high)Foxp3(+) subset, as shown in a study involving 21 normal control participants.

The mechanism by which RAPA enhances Treg involves differential regulation of signaling pathways, specifically favoring STAT5 and STAT3 phosphorylation while avoiding the PI3K/mTOR pathway, leading to increased resistance to apoptosis in Treg compared to other T cell subsets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin. Strauss, L., Czystowska, M., Szajnik, M., et al.[2021]

A new nanoparticle therapy combining rapamycin (RAPA) and a cytotoxic agent (SN38) showed enhanced effectiveness against hepatocellular carcinoma (HCC) while also improving immunosuppressive activity in organ transplantation models.

This therapy not only inhibited tumor growth but also significantly prolonged the survival of transplanted organs, suggesting it could improve outcomes for patients at high risk of tumor recurrence after organ transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A nanotherapeutic strategy that engages cytotoxic and immunosuppressive activities for the treatment of cancer recurrence following organ transplantation. Yang, Z., Xie, H., Wan, J., et al.[2023]

Sirolimus (RAPA) shows a different toxicity profile compared to cyclosporine A (CsA), primarily causing hyperlipidemia and myelodepression without the nephrotoxicity and neurotoxicity associated with CsA, making it a potentially safer option for immunosuppression in renal transplant patients.

The radioreceptor assay (RRA) for measuring RAPA levels in blood samples provides higher and more consistent results compared to the traditional HPLC method, especially in patients exhibiting toxicity, suggesting it may be a more effective tool for monitoring immunosuppression and toxicity in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radioreceptor assay for sirolimus in patients with decreased platelet counts. Goodyear, N., Napoli, KL., Murthy, JN., et al.[2019]

The combination of RAPA (rapamycin) and CsA (cyclosporine A) shows a synergistic effect in preclinical studies, suggesting that using these two immunosuppressive agents together could enhance their efficacy while potentially reducing toxicity.

Initial studies using median effect analysis in rodent and canine models indicate that this combination warrants further investigation in Phase I clinical trials to evaluate its safety and effectiveness in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of a new potent immunosuppressive agent, rapamycin. Kahan, BD., Chang, JY., Sehgal, SN.[2019]

mTOR is a promising target for cancer treatment, and several drug inhibitors, including RAP analogs like temsirolimus, everolimus, and deforolimus, are in clinical development due to RAP's limitations in solubility and stability.

Deforolimus (AP23573) has shown encouraging results in Phase I and II clinical trials for various tumors, particularly sarcoma, and is currently being evaluated in a Phase III study, indicating its potential as an effective anticancer agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. Mita, M., Sankhala, K., Abdel-Karim, I., et al.[2021]

Rapamycin can activate Akt independently of the IGF-1 receptor, indicating that intrinsic resistance to mTORC1 inhibitors in sarcomas may involve other pathways, particularly through the PDGF receptor alpha (PDGFRA).

Targeting PDGFRA in synovial sarcoma cells not only blocked the rapamycin-induced Akt activation but also reduced tumor cell viability, suggesting that combining mTORC1 inhibitors with PDGFRA inhibitors could be an effective treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PDGF receptor alpha is an alternative mediator of rapamycin-induced Akt activation: implications for combination targeted therapy of synovial sarcoma. Ho, AL., Vasudeva, SD., Laé, M., et al.[2021]

In a phase II trial involving 212 patients with advanced sarcomas, ridaforolimus demonstrated a clinical benefit response rate of 28.8%, indicating its potential effectiveness in this heavily pretreated population.

The treatment was associated with manageable side effects, primarily mild to moderate, such as stomatitis and fatigue, suggesting that ridaforolimus is a relatively safe option for patients with advanced sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. Chawla, SP., Staddon, AP., Baker, LH., et al.[2022]

Rapamycin and its derivatives, RAD001 and CCI-779, are being investigated as potential cancer treatments due to their ability to inhibit the mTOR pathway, which is crucial for cell growth regulation.

These compounds, originally developed as immunosuppressants, show promise in treating hematologic malignancies by effectively blocking cell growth, which could improve outcomes for patients who are initially responsive to chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

mTOR inhibitors in hematologic malignancies. Dancey, JE.[2021]

Rapamycin (RAPA) not only suppresses lymphocyte responses but also inhibits the activation and maturation of dendritic cells (DCs), which are crucial for T-cell stimulation, indicating a broader mechanism of action than previously understood.

In both laboratory and live models, RAPA was shown to down-regulate IL-4 receptor components and impair DC functions, suggesting its potential therapeutic implications for treating autoimmune diseases and conditions related to transplant rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin inhibits IL-4--induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Hackstein, H., Taner, T., Zahorchak, AF., et al.[2021]

References

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

Monitoring of CD8(+) T-cell Activity in mTOR Inhibitor-treated Cancer Patients for Successful Immunotherapy. [2021]

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

Immunologic and dose dependent effects of rapamycin and its evolving role in chemoprevention. [2022]

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

Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation. [2021]

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

Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. [2022]

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

Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin. [2021]

6. Netherlands pubmed.ncbi.nlm.nih.gov

A nanotherapeutic strategy that engages cytotoxic and immunosuppressive activities for the treatment of cancer recurrence following organ transplantation. [2023]

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

Radioreceptor assay for sirolimus in patients with decreased platelet counts. [2019]

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

Preclinical evaluation of a new potent immunosuppressive agent, rapamycin. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. [2021]

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

PDGF receptor alpha is an alternative mediator of rapamycin-induced Akt activation: implications for combination targeted therapy of synovial sarcoma. [2021]

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

Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. [2022]

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

mTOR inhibitors in hematologic malignancies. [2021]

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

Rapamycin inhibits IL-4--induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. [2021]