RAPA-201 Immunotherapy for Solid Cancers

Overseen By Jennifer Sunga - Regulatory Affairs Associate

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Rapa Therapeutics LLC

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

Disqualifiers: Other malignancy, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 18

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new immunotherapy, RAPA-201, for solid tumors that have recurred or spread after prior treatments. It employs reprogrammed T cells, the body's natural fighters, to enhance the immune response against cancer, aiming to improve outcomes for cancers unresponsive to previous therapies. Individuals with advanced solid tumors, such as head and neck cancer, melanoma, and certain lung cancers, who have relapsed after at least one treatment, might be suitable candidates. Participants will receive a combination of chemotherapy and RAPA-201 Rapamycin Resistant T Cells, followed by maintenance therapy, to evaluate if this approach can effectively manage their cancer.

As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that RAPA-201, a type of immunotherapy, has promising safety results from earlier studies. RAPA-201 uses special T cells, called Th1/Tc1, modified to resist a drug named temsirolimus. These cells have been safely used in outpatient settings, allowing patients to receive treatment without hospital stays.

One study described RAPA-201 as "exquisitely safe," indicating a very low risk of harm. In trials for other conditions like multiple myeloma, RAPA-201 reduced symptoms without major safety issues. Some side effects, such as high cholesterol, have been noted but are generally manageable.

Since this trial is in the early stages, the main goal is to assess the safety of RAPA-201 for people with solid tumors. These early stages are crucial for understanding safety before testing the treatment's effectiveness. Overall, the safety data so far appear encouraging for anyone considering joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for solid tumors?

Unlike the standard treatments for solid cancers, which often include chemotherapy, radiation, and surgery, RAPA-201 uses a unique approach by deploying rapamycin-resistant T cells. These engineered T cells are designed to withstand the effects of rapamycin, allowing them to persist and function effectively in the patient's body. Researchers are particularly excited because RAPA-201 offers a novel immune-based strategy that could enhance the body's ability to fight cancer, potentially leading to improved outcomes compared to traditional therapies. Additionally, the combination with anti-PD1 therapy aims to further boost immune response against the cancer cells.

What evidence suggests that RAPA-201 might be an effective treatment for solid tumors?

Research has shown promising results for RAPA-201, currently under study in this trial for treating solid tumors. In one study, 64% of patients experienced disease improvement, with eight showing some improvement and one fully recovering. Another study found that 60% of melanoma patients responded well to RAPA-201 treatment. This therapy uses special T cells that resist certain drugs and remain active longer in the body. The goal is to strengthen the immune system's ability to fight cancer. Overall, early evidence suggests that RAPA-201 could be a strong option for patients with difficult-to-treat solid tumors. ^{1 2 3 5 6}

Who Is on the Research Team?

Daniel Fowler, M.D.

Principal Investigator

Rapa Therapeutics LLC

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Chemotherapy Prior to RAPA-201 Therapy
• RAPA-201 Rapamycin Resistant T Cells

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.

How Is the Trial Designed?

Group I: Administration of RAPA-201 cells Experimental Treatment 3 Interventions

RAPA-201 cells will be administered at a target flat dose of 400 x 10\^6 cells per infusion. After RAPA-201 therapy, anti-PD1 maintenance therapy (pembrolizumab, 200 mg administered intravenously every 3 weeks for up to 12 months)

Who Is Running the Clinical Trial?

Rapa Therapeutics LLC

Lead Sponsor

Trials

6

Recruited

200+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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]

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 (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]

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]

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]

Citations

1. jitc.bmj.com jitc.bmj.com/content/13/1/e010649

Rapamycin-resistant polyclonal Th1/Tc1 cell therapy ... Nine of 14 patients (64%) achieved disease remission, with eight partial responses and one stringent complete response. Median progression-free ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06708455

Phase 2b of RAPA-201 Cell Therapy in Post-PD-(L)- ... Initial results on the first RAPA-201 clinical trial in solid tumors (NCT05144698) demonstrated that six out of 10 evaluable melanoma patients (60%) responded ...

3. cancer.gov cancer.gov/clinicaltrials/NCI-2022-01928

RAPA-201 Therapy of Solid Tumors - NCI The study evaluates adoptive T cell therapy using autologous. rapamycin-resistant Th1/Tc1 cells (RAPA-201) in the context of a standard-of-care. chemotherapy ...

4. withpower.com withpower.com/trial/phase-2-adenocarcinoma-7-2021-3af87

RAPA-201 Immunotherapy for Solid Cancers In a study involving rapamycin-resistant T cells, there was no transplant-related death, and the treatment was deemed safe, although some patients experienced ...

5. synapse.patsnap.com synapse.patsnap.com/drug/e2402a4cbcaa426a88875a563a60a33e

Autologus rapamycin resistant T-cell therapy (Rapa ... Nine of 14 patients (64%) achieved disease remission, with eight partial responses and one stringent complete response. Median progression-free survival was 6.0 ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39875173/

Rapamycin-resistant polyclonal Th1/Tc1 cell therapy ... Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma.