RP2 + Nivolumab for Eye Cancer

(RP2-202 Trial)

Recruiting at 25 trial locations

Overseen By Clinical Trials at Replimune

Age: Any Age

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Replimune Inc.

Must not be taking: Antivirals, Corticosteroids

Disqualifiers: Hepatitis, HIV, CNS involvement, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 12

Duration: Up to 3 years

280 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of a new treatment combination for metastatic uveal melanoma, a specific type of eye cancer. Researchers compare two treatment combinations: RP2 with nivolumab and nivolumab with ipilimumab, to determine which is more beneficial. RP2 is an oncolytic virus that attacks cancer cells, while nivolumab is a therapy that helps the immune system fight cancer. Individuals with metastatic uveal melanoma who have not yet received immune checkpoint inhibitor therapy might be suitable for this trial. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants the chance to contribute to significant advancements in cancer therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking systemic anticancer therapy or prior radiotherapy within 2 weeks of the first dose. Additionally, you cannot use systemic antivirals with antiherpetic activity or immunosuppressive doses of corticosteroids within 14 days after enrollment.

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

Research has shown that RP2, a virus tested to fight cancer, has been safe for people with solid tumors in early studies. Participants handled it well without major problems. Nivolumab, a drug often used for other cancers, has some known side effects. The most common one affecting the eyes is uveitis, an inflammation in the eye. However, these side effects usually do not stop the treatment.

Since this study is in later stages, earlier trials have already provided some confidence in the safety of RP2 and nivolumab. It is important to discuss any concerns with a doctor to determine if joining this trial is suitable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for eye cancer, which often involve immune checkpoint inhibitors like ipilimumab and nivolumab, the combination of RP2 and nivolumab offers a novel approach. RP2 is an oncolytic virus that selectively infects and kills cancer cells, sparking a stronger immune response against the tumor. This mechanism of action is unique because it directly targets cancer cells while simultaneously boosting the body's immune system. Researchers are excited about this treatment because it represents a dual attack on cancer, potentially leading to improved outcomes for patients with eye cancer.

What evidence suggests that this trial's treatments could be effective for eye cancer?

Research shows that RP2, a virus designed to attack and kill cancer cells, holds promise for treating metastatic uveal melanoma, a type of eye cancer. In this trial, participants in the test arm will receive RP2 combined with nivolumab, a drug that helps the immune system fight cancer. Early results suggest that this combination is safe and can shrink tumors. Studies indicate that RP2 enhances the effectiveness of immune therapies in treating difficult tumors. This combination has demonstrated significant activity against tumors, offering hope for patients with this challenging eye cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Rahul Marpadga, MD MPH

Principal Investigator

Replimune Inc.

Are You a Good Fit for This Trial?

Adults over 18 with metastatic uveal melanoma, who haven't had immune checkpoint inhibitor therapy, can join. They should be able to perform daily activities (ECOG PS 0 or 1), have tumors suitable for RP2 injections and biopsies, normal LDH levels, good blood clotting, and organ function. Life expectancy must be more than 6 months.

Inclusion Criteria

I have been diagnosed with a type of eye cancer that cannot be removed with surgery.

I have a tumor or lymph node big enough for injection treatment.

My LDH levels are within twice the normal upper limit.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either RP2 in combination with nivolumab or ipilimumab in combination with nivolumab

Up to 3 years

Every 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

100 days

What Are the Treatments Tested in This Trial?

Interventions

• RP2

Trial Overview The trial is testing the effectiveness of a new treatment combo: RP2 plus nivolumab against an existing combo: nivolumab plus ipilimumab in patients with advanced eye cancer. It aims to see which combination works better for those who haven't tried these therapies before.

How Is the Trial Designed?

Group I: Test Arm: RP2 + nivolumab Experimental Treatment 2 Interventions

RP2 (Oncolytic virus) and Nivolumab (programmed death receptor-1 (PD-1) inhibitor)

Group II: Control Arm (Active Comparator): ipilimumab + nivolumab Experimental Treatment 2 Interventions

Immune Checkpoint inhibitor combination

Who Is Running the Clinical Trial?

Replimune Inc.

Lead Sponsor

Trials

16

Recruited

1,700+

Published Research Related to This Trial

In a study of 19 gastric cancer patients receiving third-line nivolumab therapy, only 15.8% showed durable clinical benefit, indicating limited efficacy in this advanced treatment setting.

High T cell to regulatory T cell (Treg) ratios and specific gene expression signatures were associated with better treatment responses, suggesting these could serve as potential biomarkers for selecting patients who may benefit from nivolumab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alterations in Intratumoral Immune Response before and during Early-On Nivolumab Treatment for Unresectable Advanced or Recurrent Gastric Cancer. Sato, Y., Yamashita, H., Kobayashi, Y., et al.[2023]

PD-L1 is constitutively expressed in most human ocular cell lines and is significantly upregulated in inflamed ocular tissues, suggesting its role in regulating ocular inflammation.

Blocking PD-L1 enhances the production of proinflammatory cytokines by T cells, indicating that PD-L1 may help maintain immune privilege in the eye by inhibiting excessive immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-L1 expression on human ocular cells and its possible role in regulating immune-mediated ocular inflammation. Yang, W., Li, H., Chen, PW., et al.[2022]

Loss of the retinoblastoma (Rb) tumor suppressor is linked to non-T-cell-inflamed tumor microenvironments, which are less responsive to immune checkpoint blockade (ICB), as shown in both human tumors and murine models.

Inhibition of bromodomain and extraterminal (BET) proteins using JQ1 can enhance immune cell infiltration and reprogram the cold tumor microenvironment, making Rb-deficient prostate cancer more sensitive to ICB, suggesting a promising combination therapy for clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BET Inhibition Sensitizes Immunologically Cold Rb-Deficient Prostate Cancer to Immune Checkpoint Blockade. Olson, BM., Chaudagar, K., Bao, R., et al.[2023]

The oncolytic virus HSV-1-EGFP demonstrated significant antitumor efficacy in uveal melanoma (UM) by reducing both intraocular and systemic tumors in murine models, indicating its potential as a targeted treatment option.

Treatment with oHSV-EGFP led to a favorable immune response, characterized by increased anti-tumor M1 macrophages and natural killer cells, while showing no viral presence in major organs, suggesting a safe profile for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Macrophage polarization contributes to the efficacy of an oncolytic HSV-1 targeting human uveal melanoma in a murine xenograft model. Liu, S., Zhang, J., Fang, S., et al.[2021]

In a study of 262 retinoblastoma cases, the expression of immune checkpoint markers PD-1 and PD-L1 varied significantly between primary and chemoreduced tumors, indicating different tumor microenvironments that could influence treatment strategies.

The presence of PD-L1 in primary retinoblastoma and PD-1 in chemoreduced retinoblastoma were associated with poorer overall survival rates, suggesting these markers could serve as important prognostic indicators and potential therapeutic targets for chemoresistant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical relevance of the comparative expression of immune checkpoint markers with the clinicopathological findings in patients with primary and chemoreduced retinoblastoma. Singh, L., Singh, MK., Rizvi, MA., et al.[2020]

RPE (retinal pigment epithelium) cells increase the expression of PD-L1 in response to inflammatory cytokines like IL-17 and IFN-γ, which helps inhibit the harmful activities of T cells that can cause uveitis.

The presence of PD-L1 on RPE cells not only suppresses the pathogenicity of T cells but also promotes regulatory activities that can help resolve inflammation in the eye, suggesting a potential therapeutic mechanism for managing uveitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-L1(hi) retinal pigment epithelium (RPE) cells elicited by inflammatory cytokines induce regulatory activity in uveitogenic T cells. Ke, Y., Sun, D., Jiang, G., et al.[2021]

A novel retinoblastoma (RB) immunotherapy model was successfully developed using human peripheral blood lymphocytes in NOD-SCID mice, allowing for the study of human-like tumor behavior and immune responses.

The model demonstrated that human lymphocytes could be present in the tumors and spleens of the mice, indicating potential for investigating immune regression and immunotherapy strategies for treating human retinoblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Establishment of human retinoblastoma model in human immune reconstruction non-obese diabetic-severe combine immunodeficient mice]. Zhong, XF., Ge, J., Peng, FH., et al.[2007]

The study developed two new oncolytic herpes simplex virus (HSV-1) variants, with T-mfIL12 showing significantly higher production of interleukin 12 (IL-12) compared to T-mIL12-IRES, enhancing its potential as a cancer treatment.

In mouse models, T-mfIL12 demonstrated greater efficacy in reducing tumor growth and eliciting stronger antitumor immune responses, indicating that the method of IL-12 expression can significantly impact the effectiveness of oncolytic virus therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fusion peptide is superior to co-expressing subunits for arming oncolytic herpes virus with interleukin 12. Fukuhara, H., Sato, YT., Hou, J., et al.[2023]

Retinoblastoma cells express GD2, which is associated with tumor growth and staging, making it a promising target for immunotherapy using NK cells.

The combination of dinutuximab and CD16-expressing NK-92MI cells significantly enhances the destruction of retinoblastoma cells through mechanisms like antibody-dependent cell-mediated cytotoxicity, indicating a potential new treatment strategy for advanced cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dinutuximab Synergistically Enhances the Cytotoxicity of Natural Killer Cells to Retinoblastoma Through the Perforin-Granzyme B Pathway. Wang, H., Yang, J., Pan, H., et al.[2022]

Next-generation oncolytic herpes simplex viruses (oHSVs) that are retargeted to HER2 receptors showed a high safety profile and effectively inhibited tumor growth in immunocompetent mice, with the IL-12-armed variant (R-115) being particularly more efficacious.

The treatment not only targeted the primary tumors but also provided protection against untreated tumors, indicating a systemic immunotherapeutic effect and a potential for long-term immunity against cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fully-virulent retargeted oncolytic HSV armed with IL-12 elicits local immunity and vaccine therapy towards distant tumors. Leoni, V., Vannini, A., Gatta, V., et al.[2022]

Nivolumab, a PD-1 inhibitor, has demonstrated significant safety and efficacy in treating various advanced solid tumors, including melanoma and lung cancer, based on multiple high-level studies.

Future research should aim to identify predictive biomarkers for treatment response and explore the potential of combining nivolumab with other therapies, as well as determining the best treatment strategies and duration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the pharmacodynamics, pharmacokinetics, safety and clinical efficacy of nivolumab in the treatment of solid cancers. Wong, AC., Ma, B.[2018]

Citations

1. ir.replimune.com ir.replimune.com/news-releases/news-release-details/replimune-announces-rp2-development-program-advances-first

Replimune Announces RP2 Development Program ... The first patients have been enrolled in studies evaluating RP2 in two different settings: checkpoint naïve metastatic uveal melanoma; and second-line ...

2. asco.org asco.org/abstracts-presentations/ABSTRACT401600

Preliminary safety and efficacy results from an open-label ... Preliminary RP2 monotherapy and RP2 + nivo data demonstrated a favorable safety profile and meaningful antitumor activity in pts with metastatic uveal melanoma.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6880119/

Enhanced Therapeutic Efficacy of a Novel Oncolytic Herpes ... The efficacy of immune checkpoint blockade therapy against immunologically “cold” tumors can be enhanced by applying the checkpoint inhibitors in combination ...

4. nature.com nature.com/articles/s41598-024-72888-w

Improved antitumor effectiveness of oncolytic HSV-1 ... Oncolytic viruses derived from herpes simplex virus-1 (oHSVs) exhibit substantial promise as a potential cancer treatment option. HSV-1's broad ...

5. vjoncology.com vjoncology.com/video/q9mtyx6rv7q-rp2-engineered-oncolytic-herpes-simplex-virus-for-durable-responses-in-metastatic-uveal-melanoma/

ASCO 2024 | RP2: engineered oncolytic herpes simplex virus ... RP2, an oncolytic herpes simplex virus engineered to enhance immunogenicity and promote durable responses in metastatic uveal melanoma (MUM).

6. opdivo.com opdivo.com/clinical-trial-results

Clinical Trial Results Select your cancer type above to see how OPDIVO, alone or in combination with other therapies, performed in clinical trials.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9947214/

Ocular adverse events associated with immune checkpoint ... The primary used ICIs were nivolumab (n = 123; 42.5%) and ipilimumab (n = 116; 40.0%). Uveitis was most the common adverse event (n = 134; 46.2 ...

8. nature.com nature.com/articles/s41433-024-03212-z

Impact of immune checkpoint inhibitors on vision and eye ... Moreover, the combination of ipilimumab with nivolumab, an anti-PD-1 agent, resulted in 59% rate of grade 3-4 irAEs compared to a rate of 21–28% ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8130843/

Ocular Adverse Events following Use of Immune Checkpoint ... We found a wide spectrum of ocular irAEs associated with immune checkpoint inhibitors. In most cases, ocular AEs did not limit ongoing cancer treatment.

10. sciencedirect.com sciencedirect.com/science/article/pii/S0959804919304101

Safety and efficacy of nivolumab in patients with rare ... Median overall survival was 12.6 months for ocular melanoma and 11.5 months for mucosal melanoma, with 18-month overall survival rates of 34.8% and 31.5%, ...