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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments: AL3818 (anlotinib, a cancer drug) and Opdivo (nivolumab, an immunotherapy), to determine their safety and efficacy for individuals with difficult-to-treat cancers. It targets cancers such as soft tissue sarcomas and lung cancer that have not responded well to previous treatments. The study consists of two parts: first, determining the appropriate dose, and second, evaluating the combination's effectiveness. Suitable participants have previously undergone cancer treatments but still experience tumor growth or recurrence. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and to measure its effectiveness in an initial, smaller group.

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.

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

Previous studies have shown that the combination of AL3818 (anlotinib) and nivolumab is generally safe, though it may cause some side effects. Nivolumab, also known as Opdivo, can lead to immune-related side effects, where the immune system might mistakenly attack normal organs.

Research on AL3818 combined with nivolumab remains limited, but patients in earlier trials tolerated it reasonably well. These studies help determine the right doses to minimize side effects.

While researchers continue to test this treatment combination, nivolumab has FDA approval for other conditions, offering some reassurance about its safety. As with any trial, discussing potential risks and benefits with the study team is crucial before deciding to participate. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about AL3818 combined with Nivolumab because it offers a new approach to cancer treatment by combining an anti-angiogenic agent with an immune checkpoint inhibitor. Unlike standard treatments like chemotherapy or existing immunotherapies, AL3818 works by blocking blood vessel growth that tumors need to grow, while Nivolumab helps the immune system recognize and attack cancer cells. This dual mechanism could potentially offer more effective cancer control with possibly fewer side effects. Additionally, the oral administration of AL3818 provides a convenient option for patients, which is a significant advantage over some current treatment regimens.

What evidence suggests that AL3818 plus nivolumab could be an effective treatment for solid tumors?

Research shows that using AL3818 (anlotinib) with nivolumab, as studied in this trial, may help treat various types of cancer. Studies have found that combining nivolumab with other drugs can improve cancer treatment outcomes compared to using nivolumab alone. Nivolumab is already approved for many cancers and has proven effective. Anlotinib works by stopping the growth of blood vessels that tumors need to grow. This combination aims to harness the strengths of both drugs to fight cancer more effectively. While specific results on this combination are still under investigation, the success of each drug individually supports their combined use in this trial. ^{1 2 3 6 7}

Who Is on the Research Team?

Sant P Chawla, MD

Principal Investigator

Sarcoma Oncology Research Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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, 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, 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 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 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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04165330?spons=COVERAGE%5BFullMatch%5DEXPANSION%5BNone%5D(%22Advenchen%20Laboratories,%20LLC%22)&viewType=Table&rank=1

Evaluation of AL3818 in Combination With Nivolumab ... This phase 1b/2 study evaluates the safety and efficacy of AL3818 (anlotinib) hydrochloride in combination with Opdivo (nivilumab) for the treatment patients ...

2. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04165330/

Clinical Trial: NCT04165330 This study evaluates the safety and efficacy of AL3818 (anlotinib) hydrochloride in combination with Opdivo (nivilumab) for the treatment ...

3. withpower.com withpower.com/trial/phase-2-small-cell-lung-carcinoma-9-2019-edc77

AL3818 + Nivolumab for Cancer · Info for Participants Combining nivolumab with ipilimumab results in higher response rates in cancer treatment compared to using nivolumab alone, indicating a potentially more ...

4. opdivohcp.com opdivohcp.com/efficacy

Efficacy Information | OPDIVO® (nivolumab) OPDIVO® (nivolumab), alone or in combination, is approved in 25 indications. Discover the robust evidence behind the use of OPDIVO from earlier to advanced ...

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

Clinical Trial Results OPDIVO® (nivolumab) immunotherapy alone, or in combination with other therapies works to help fight many types of cancer. Access OPDIVO® clinical trial ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7656422/

Combinational immunotherapy based on immune ... Emerging combinational immunotherapy will transform SCLC into a chronic disease to help patients survive from tumors.

7. opdivo.com opdivo.com/nsclc/clinical-trial-results/advanced-immunotherapy-combination-chemo

For adults with advanced non-small cell lung cancer ... An FDA-approved combination of two immunotherapies with limited chemotherapy that helped people live longer compared to platinum-based chemotherapy.