Extended vs Standard Dosing for Immunotherapy in Cancer

Recruiting at 1 trial location

Overseen By Personalized Cancer Care Consortium

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Chicago

Must be taking: Nivolumab, Pembrolizumab

Must not be taking: Ipilimumab

Disqualifiers: Immune checkpoint inhibitors, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 2 years

264 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if the cancer treatments nivolumab (Opdivo) and pembrolizumab (KEYTRUDA or MK-3475) can be administered less frequently without losing effectiveness. It will compare the standard dosing schedule to an extended schedule to assess the necessary frequency of medication for patients. Individuals with locally advanced or metastatic cancer who are already candidates for these treatments might be suitable for the trial. Participants should not have previously received similar immune therapies or plan to take certain drug combinations.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Studies have shown that both nivolumab and pembrolizumab are generally well-tolerated by patients. Research indicates that switching to longer intervals between doses does not increase the risk of side effects. Specifically, studies confirm that taking nivolumab less often is just as safe as the regular schedule, with no increase in side effects. Similarly, for pembrolizumab, taking it less often does not lead to a higher risk of immune-related side effects. Overall, the safety of these longer schedules aligns with expectations from regular dosing. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the immunotherapy dosing trial because it explores the potential benefits of extended interval dosing for cancer treatments, specifically using nivolumab and pembrolizumab. Unlike the standard treatment schedule, which involves more frequent administrations, this trial investigates whether less frequent dosing can maintain effectiveness while potentially reducing side effects and improving patient convenience. By modifying the dosing schedule, researchers hope to enhance the quality of life for patients without compromising the efficacy of the treatment. This approach could represent a significant shift in how immunotherapy is delivered, offering a more patient-friendly option.

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

This trial will compare extended interval dosing with standard interval dosing for immunotherapy in cancer. Studies have shown that both nivolumab and pembrolizumab effectively treat various cancer types. Research suggests that administering nivolumab less frequently can still be effective and might enhance patients' quality of life. Similarly, less frequent dosing of pembrolizumab does not appear to increase severe side effects compared to more frequent dosing, indicating it can be just as safe and effective. Early evidence suggests that spreading out doses for both treatments might still control cancer effectively, allowing patients to receive treatment less often without losing its benefits. ^{1 4 5 6 7}

Who Is on the Research Team?

Mark Ratain, MD

Principal Investigator

University of Chicago

Are You a Good Fit for This Trial?

This trial is for adults with measurable, advanced or metastatic cancer who are candidates for nivolumab or pembrolizumab treatment. It's not open to those who've had immune checkpoint inhibitors before, or plan to combine these drugs with ipilimumab or other anti-CTLA4 antibodies.

Inclusion Criteria

My doctor recommends nivolumab or pembrolizumab for my advanced cancer.

Measurable disease per RECIST criteria

Exclusion Criteria

I am not planning to receive both ipilimumab and nivolumab for my treatment.

My treatment plan includes ipilimumab with nivolumab or pembrolizumab.

I have received treatments like immune checkpoint inhibitors or experimental antibody therapy before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either standard interval dosing or extended interval dosing of nivolumab or pembrolizumab

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Pembrolizumab

Trial Overview The study tests if nivolumab and pembrolizumab can be given less frequently than the current standard without affecting drug levels in the blood. Patients will receive either extended interval dosing or standard dosing of these medications.

How Is the Trial Designed?

Group I: standard interval dosing Experimental Treatment 2 Interventions

Group II: extended interval dosing Experimental Treatment 2 Interventions

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Published Research Related to This Trial

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

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]

In a study involving 1,453 patients with advanced melanoma and non-small cell lung cancer (NSCLC), pembrolizumab showed no dependency on dosage for overall survival, indicating that varying doses (2 to 10 mg/kg) did not significantly affect patient outcomes.

A strong association was found between the baseline clearance (CL0) of pembrolizumab and overall survival, suggesting that higher clearance rates may indicate more severe disease, rather than affecting the drug's efficacy directly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Exposure-Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance. Turner, DC., Kondic, AG., Anderson, KM., et al.[2019]

In a study of 71 melanoma patients, the incidence of immune-related adverse events (IrAEs) was similar between those receiving nivolumab every 2 weeks (40%) and those receiving it every 4 weeks (50%), indicating that extended dosing is as safe as the original regimen.

Patients on the Q4W dosing experienced a potentially later onset of IrAEs, and most adverse events were mild (grade 1-2), suggesting that Q4W dosing not only maintains safety but also reduces the frequency of clinic visits and patient exposure to viruses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utilization and toxicity patterns of 2-weekly (Q2W) versus 4-weekly (Q4W) nivolumab for treatment of adjuvant and metastatic melanoma at BC cancer. Truong, J., Yeung, SST., Kletas, V., et al.[2023]

In a study of 69 patients with solid tumors receiving extended dosing intervals of nivolumab or pembrolizumab, 21.7% developed immune-related adverse events (irAEs), particularly during the first cycle of treatment.

Patients with pre-existing anti-thyroid antibodies were found to have a significantly higher risk of developing irAEs after starting extended dosing intervals, indicating that these patients should be monitored closely during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world study on the safety of the extended dosing schedule for nivolumab and pembrolizumab in patients with solid tumors. Morimoto, K., Yamada, T., Morimoto, Y., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

The REFINE-Lung study (NCT05085028) is a UK multicentre phase 3 trial that aims to optimize the dosing frequency of pembrolizumab, an anti-PD-1 therapy, for patients with advanced non-small-cell lung cancer, addressing concerns about overtreatment and its associated costs and side effects.

This study employs a novel multi-arm multi-stage response over continuous interventions (MAMS-ROCI) design, which allows for more efficient exploration of multiple dosing strategies compared to traditional trial designs, potentially leading to significant improvements in patient care and treatment optimization across various cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

REFINE-Lung implements a novel multi-arm randomised trial design to address possible immunotherapy overtreatment. Ghorani, E., Quartagno, M., Blackhall, F., et al.[2023]

In a study of patients with advanced melanoma, the combination of pembrolizumab and ipilimumab showed significant antitumor activity, with objective response rates of 55% for the 50 mg ipilimumab regimen and 61% for the 100 mg regimen, indicating effective treatment options.

The 50 mg ipilimumab regimen resulted in a lower incidence of severe treatment-related adverse events (24%) compared to the 100 mg regimen (39%), suggesting that this combination may offer a safer alternative with reduced toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Standard-Dose Pembrolizumab Plus Alternate-Dose Ipilimumab in Advanced Melanoma: KEYNOTE-029 Cohort 1C, a Phase 2 Randomized Study of Two Dosing Schedules. Long, GV., Robert, C., Butler, MO., et al.[2023]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Personalized dosing of pembrolizumab at 2 mg/kg could save approximately $825 million annually in the United States compared to the fixed dosing of 200 mg every three weeks, without negatively affecting treatment outcomes.

The study analyzed the economic impact of dosing strategies for pembrolizumab in metastatic non-small cell lung cancer, estimating costs based on patient weight and survival data from the KEYNOTE 024 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phamacoeconomic Analysis of Personalized Dosing vs Fixed Dosing of Pembrolizumab in Firstline PD-L1-Positive Non-Small Cell Lung Cancer. Goldstein, DA., Gordon, N., Davidescu, M., et al.[2022]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Citations

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Extending the dosing intervals of nivolumab: model-based ... Reducing nivolumab dose intensity could increase patients' life quality and decrease the financial burden while maintaining efficacy.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.2595

Extended interval dosing in patients with cancer receiving ... Results: Among 756 pts enrolled in the EDICI study, 733 pts (229 treated with pembrolizumab, and 504 with nivolumab) were included in the final ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1567576922002594

A real-world study on the safety of the extended dosing ... This real-world study enrolled patients with solid tumors who received nivolumab 480 mg every 4 weeks or pembrolizumab 400 mg every 6 weeks.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04295863

NCT04295863 | Comparing Dosing Intervals of Nivolumab ... This trial will compare drug levels from the blood from standard interval dosing levels versus taking the drugs less often.

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-13885

Standard Interval Dosing Compared to Extended ... This phase I trial compares the drug levels of the standard dosing schedule (of either nivolumab or pembrolizumab) to an extended interval dosing schedule.

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Comparison of clinical safety between standard versus ... A real-world study on the safety of the extended dosing schedule for nivolumab and pembrolizumab in patients with solid tumors. Int ...

7. academic.oup.com academic.oup.com/jnci/article/115/7/796/7115841

Safety of extended interval dosing immune checkpoint inhibitors Switching ICI treatment from CD and ED did not increase the incidence of irAEs and represents a safe option also outside clinical trials. Topic:.