RP2 + Nivolumab for Eye Cancer

(RP2-202 Trial)

Recruiting at 18 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?

The purpose of this study is to measure the clinical benefits of the combination of RP2 and nivolumab as compared with the combination of nivolumab and ipilimumab in patients with metastatic uveal melanoma who have not been treated with immune checkpoint inhibitor 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 the RP2 + Nivolumab treatment safe for humans?

Research on similar treatments using oncolytic herpes simplex virus (HSV) in eye cancers like uveal melanoma suggests they are generally safe, as no virus was detected in major organs after treatment, indicating limited spread beyond the targeted area. ^{1 2 3 4 5}

What makes the RP2 + Nivolumab treatment unique for eye cancer?

RP2 is an enhanced oncolytic herpes simplex virus that specifically targets and destroys cancer cells, while Nivolumab is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells. This combination is unique because it uses a virus to directly kill cancer cells and boosts the immune response, offering a novel approach compared to traditional treatments. ^{2 6 7 8 9}

What data supports the effectiveness of the treatment RP2 + Nivolumab for eye cancer?

Nivolumab, part of the treatment, is effective in treating several types of solid cancers like melanoma and lung cancer by blocking a protein that stops the immune system from attacking cancer cells. Additionally, oncolytic herpes viruses, similar to RP2, have shown promise in treating other cancers by directly killing cancer cells and stimulating the immune system. ^{1 6 7 10 11}

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

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]

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]

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]

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]

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]

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]

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]

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]

Citations

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

Fusion peptide is superior to co-expressing subunits for arming oncolytic herpes virus with interleukin 12. [2023]

2. Germany 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. [2020]

3. England pubmed.ncbi.nlm.nih.gov

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

4. China pubmed.ncbi.nlm.nih.gov

[Establishment of human retinoblastoma model in human immune reconstruction non-obese diabetic-severe combine immunodeficient mice]. [2007]

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

PD-L1 expression on human ocular cells and its possible role in regulating immune-mediated ocular inflammation. [2022]

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

BET Inhibition Sensitizes Immunologically Cold Rb-Deficient Prostate Cancer to Immune Checkpoint Blockade. [2023]

7. England 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. [2021]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Dinutuximab Synergistically Enhances the Cytotoxicity of Natural Killer Cells to Retinoblastoma Through the Perforin-Granzyme B Pathway. [2022]

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

A fully-virulent retargeted oncolytic HSV armed with IL-12 elicits local immunity and vaccine therapy towards distant tumors. [2022]

10. England pubmed.ncbi.nlm.nih.gov

PD-L1(hi) retinal pigment epithelium (RPE) cells elicited by inflammatory cytokines induce regulatory activity in uveitogenic T cells. [2021]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Alterations in Intratumoral Immune Response before and during Early-On Nivolumab Treatment for Unresectable Advanced or Recurrent Gastric Cancer. [2023]