AL3818 + Nivolumab for Cancer

Overseen By Sant P Chawla, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Sarcoma Oncology Research Center, LLC

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: CNS metastases, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: 5

56 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking any prior anti-cancer therapy at least 21 days before starting the study treatment. Additionally, you must not be on systemic corticosteroids or other immunosuppressive medications within 14 days before starting the trial.

What data supports the effectiveness of the drug Nivolumab in treating cancer?

Nivolumab has shown effectiveness in treating various cancers, including non-small cell lung cancer (NSCLC), melanoma, and renal cell cancer, by helping the immune system attack cancer cells. It has been associated with better survival rates and response rates compared to some other treatments, and it is generally well-tolerated. ^{1 2 3 4 5}

Is the combination of AL3818 and Nivolumab safe for humans?

Nivolumab, also known as Opdivo, is generally safe but can cause immune-related side effects, which are reactions where the immune system attacks normal organs and tissues. These side effects have been observed in treatments for various cancers, including melanoma and renal cell carcinoma. ^{6 7 8 9 10}

What makes the drug AL3818 + Nivolumab unique for cancer treatment?

The combination of AL3818 and Nivolumab is unique because it pairs a novel treatment with a programmed death-1 (PD-1) immune checkpoint inhibitor, which helps the immune system recognize and attack cancer cells. Nivolumab has shown effectiveness in various cancers by blocking the PD-1 pathway, enhancing T-cell activity against tumors. ^{1 2 4 11 12}

What is the purpose of this trial?

This trial is testing a new drug called AL3818 with Opdivo to treat patients with very advanced or returning cancers. AL3818 stops blood supply to tumors, while Opdivo helps the immune system attack cancer cells.

Research Team

Sant P Chawla, MD

Principal Investigator

Sarcoma Oncology Research Center

Eligibility Criteria

This trial is for adults with certain advanced solid tumors, including lung cancer and sarcoma, who've had at least one previous treatment. They must have a good performance status (able to carry out daily activities), proper organ function, controlled blood pressure, no major recent surgeries or untreated brain metastases, and not be on immunosuppressants.

Inclusion Criteria

I am able to care for myself and perform daily activities.

My condition worsened or came back within the last 6 months.

Life expectancy of ≥ 3 months at the time of enrollment.

Exclusion Criteria

I do not have any autoimmune or lung diseases.

My cancer has spread to the lining of my brain and spinal cord.

I have hepatitis C and haven't completed treatment, with a detectable viral load.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Finding

Participants receive AL3818 and nivolumab to determine the recommended phase 2 dosage

3 weeks

2 visits (in-person)

Dose Expansion

Participants receive AL3818 at the RP2D with nivolumab to evaluate safety and efficacy

18 months

Every 3 weeks for up to 24 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Treatment Details

Interventions

• AL3818
• Nivolumab

Trial Overview The study tests AL3818 combined with Nivolumab in patients with advanced solid tumors. It has two parts: first to find the best dose of AL3818 when used with Nivolumab; second to check how safe and effective this combination is in treating different types of cancers like soft tissue sarcoma and lung cancer.

Participant Groups

Group I: AL3818 plus nivolumab Experimental Treatment 2 Interventions

Part 1: All participants will be assigned to receive AL3818 capsules orally, once daily at sequential deescalating doses (on treatment Days 1-14 followed by no AL3818 treatment from Days 15-21) in combination with nivolumab injection treatment (on Day 1 and Day 15) for a single 21-day cycle. Participants may continue study treatment at the AL3818 cohort dose at investigator discretion. Part 2: All participants will receive AL3818 capsules orally, once daily at the RP2D determined from Part 1 (on treatment Days 1-14 followed by no AL3818 treatment from Days 15-21) in combination with nivolumab injection treatment (every 2 weeks starting on Cycle 1, Day 1) in 21-day cycles, for up to 24 cycles of total AL3818 therapy.

Who Is Running the Clinical Trial?

Sarcoma Oncology Research Center, LLC

Lead Sponsor

Trials

9

Recruited

910+

Advenchen Laboratories, LLC

Industry Sponsor

Trials

6

Recruited

850+

Findings from Research

Nivolumab, an anti-PD-1 antibody, was administered to a 63-year-old female patient with metastatic melanoma after renal transplantation, highlighting the potential for anti-tumor activity in high-risk patients, despite the challenges of concurrent immunosuppression.

The patient experienced acute renal allograft rejection and renal failure shortly after starting nivolumab, indicating significant risks associated with this treatment in transplant recipients, but she later showed a positive clinical response after re-challenging with nivolumab while on hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. Ong, M., Ibrahim, AM., Bourassa-Blanchette, S., et al.[2023]

Nivolumab and pembrolizumab are FDA-approved monoclonal antibodies that target PD-1, helping to enhance T cell activity against cancer by blocking the PD-1/PD-L1 interaction, which allows cancer cells to escape immune detection.

Both drugs have shown efficacy across multiple cancer types, including melanoma and non-small cell lung cancer, and are considered interchangeable options for treating these conditions, which may help manage the rising costs of cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. Prasad, V., Kaestner, V.[2022]

Combining nivolumab with ipilimumab results in higher response rates in cancer treatment compared to using nivolumab alone, indicating a potentially more effective therapeutic strategy.

This combination therapy may enhance the immune response against cancer, but specific details on the number of subjects or study duration are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

Nivolumab, an immune checkpoint inhibitor, significantly improved overall survival and progression-free survival compared to docetaxel in patients with advanced squamous non-small cell lung cancer (NSCLC) in the CheckMate 017 trial.

Nivolumab was better tolerated than docetaxel, with manageable adverse effects, making it a promising treatment option for patients who have already undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. Keating, GM.[2022]

Nivolumab, a PD-1 receptor inhibitor, shows an objective response rate of 18% and a 1-year overall survival rate of 45% in patients with advanced non-small-cell lung cancer, based on a meta-analysis of 20 studies involving 3404 patients.

The presence of PD-L1 expression in patients is associated with a better response to nivolumab, indicating that PD-L1 status can help predict treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The benefit and risk of nivolumab in non-small-cell lung cancer: a single-arm meta-analysis of noncomparative clinical studies and randomized controlled trials. Zhao, B., Zhang, W., Yu, D., et al.[2019]

Nivolumab and pembrolizumab, both PD-1 inhibitors, show a lower risk of severe treatment-related adverse effects (AEs) compared to standard care, with a relative risk of 0.39 for grade 3/4 AEs based on a meta-analysis of 9 trials involving 5,353 patients.

While these therapies are generally well tolerated, they are associated with a significantly increased risk of thyroid dysfunction (hyperthyroidism and hypothyroidism) and skin conditions like pruritus and vitiligo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials. Costa, R., Carneiro, BA., Agulnik, M., et al.[2022]

Nivolumab, an immune checkpoint inhibitor, shows strong antitumor activity but is associated with immune-related adverse events that can affect patient safety and treatment continuation, necessitating careful monitoring.

Long-term safety data, including a 5-year follow-up, suggests that nivolumab can be safely administered to various challenging patient subgroups, but identifying biomarkers for severe toxicity could improve patient selection for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the safety of nivolumab for the treatment of advanced melanoma. Czarnecka, AM., Rutkowski, P.[2021]

In the phase III CheckMate 238 trial, 67.7% of patients receiving nivolumab experienced treatment-related adverse events (TRAEs), with the most common being pruritus and diarrhea, primarily occurring within the first 3 months of treatment.

Despite the high incidence of TRAEs, there was no significant association found between these adverse events and recurrence-free survival (RFS), indicating that the safety profile of nivolumab remains consistent and does not negatively impact long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival. Mandala, M., Larkin, J., Ascierto, PA., et al.[2022]

In a study of 53 patients with metastatic renal cell carcinoma treated with nivolumab, those who experienced immune-related adverse events (irAEs) had significantly better overall survival compared to those without irAEs, indicating a potential link between irAEs and treatment efficacy.

The study found that a lower platelet-to-lymphocyte ratio before treatment was a risk factor associated with the development of irAEs, suggesting that this ratio could be a useful predictor for monitoring patient responses to nivolumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Immune-related Adverse Events and Clinical Outcome Following Nivolumab Treatment in Patients With Metastatic Renal Cell Carcinoma. Kobayashi, K., Iikura, Y., Hiraide, M., et al.[2021]

In a study of 47 patients with metastatic renal cell carcinoma treated with nivolumab, 48.9% experienced immune-related adverse events (irAEs), with rash being the most common.

Patients who developed irAEs had significantly longer progression-free survival (13.1 months vs. 4.87 months) and overall survival (26.0 months vs. not reached) compared to those without irAEs, indicating that the presence of irAEs may be a positive prognostic factor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab. Ishihara, H., Takagi, T., Kondo, T., et al.[2020]

Nivolumab, an immune checkpoint inhibitor, can lead to serious endocrine side effects, such as primary hypothyroidism, as seen in a case study of a young melanoma patient who developed symptoms after 12 weeks of treatment.

The patient's hypothyroidism was effectively managed with hormone replacement therapy, allowing him to continue nivolumab treatment safely, which underscores the importance of recognizing and managing endocrine-related adverse events to maintain patient safety and treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab-induced hypothyoidism with consequent hypothyroid related myopathy. Johnson, ED., Kerrigan, K., Butler, K., et al.[2020]

Nivolumab showed antitumor activity in patients with metastatic renal cell carcinoma (mRCC), with median overall survival rates of 18.2, 25.5, and 24.7 months across three different doses, indicating its potential effectiveness as a treatment option.

The safety profile of nivolumab was manageable, with fatigue being the most common side effect; however, no significant dose-response relationship was found in terms of progression-free survival, suggesting that the efficacy may not increase with higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. Motzer, RJ., Rini, BI., McDermott, DF., et al.[2022]

References

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

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. [2023]

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

Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. [2022]

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

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

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

Nivolumab: a review in advanced squamous non-small cell lung cancer. [2022]

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

The benefit and risk of nivolumab in non-small-cell lung cancer: a single-arm meta-analysis of noncomparative clinical studies and randomized controlled trials. [2019]

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

Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials. [2022]

7. England pubmed.ncbi.nlm.nih.gov

An update on the safety of nivolumab for the treatment of advanced melanoma. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival. [2022]

9. Greece pubmed.ncbi.nlm.nih.gov

Association Between Immune-related Adverse Events and Clinical Outcome Following Nivolumab Treatment in Patients With Metastatic Renal Cell Carcinoma. [2021]

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

Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab. [2020]

11. England pubmed.ncbi.nlm.nih.gov

Nivolumab-induced hypothyoidism with consequent hypothyroid related myopathy. [2020]

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

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. [2022]