De-intensified Radiation Therapy + Cisplatin/Nivolumab for Oropharyngeal Cancer

Not currently recruiting at 563 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Metastatic disease, Autoimmune diseases, 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: 1

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a lower dose of radiation therapy combined with either cisplatin (a chemotherapy drug) or nivolumab (an immunotherapy treatment) can effectively treat early-stage HPV-positive oropharyngeal cancer. The goal is to determine if these treatments are as effective as the standard approach, which uses a higher radiation dose with cisplatin. It targets individuals with HPV-positive cancer in the throat area who have a minimal smoking history. Participants should have noticeable disease in the oropharynx (throat area) without distant metastasis.

As a Phase 2, Phase 3 trial, this study measures the treatment's effectiveness in an initial group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on systemic corticosteroids or other immunosuppressive medications, you may need to stop them at least 14 days before joining the trial.

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

Research has shown that using a lower dose of radiation with the drug cisplatin for treating HPV-positive throat cancer is generally well-tolerated. In one study, over 96% of patients survived for at least two years, which is encouraging. However, some patients experienced more severe side effects, such as nausea or tiredness, which are serious but manageable with medical care.

For the treatment combining lower-dose radiation with nivolumab, studies provide less detailed information. Nivolumab, an FDA-approved immunotherapy drug for other types of cancer, is generally safe. However, it can cause side effects like tiredness, skin rash, or diarrhea. Since this trial tests both reduced radiation and nivolumab together, the safety of this combination remains under study.

Overall, both treatment options are being tested to ensure safety and effectiveness. While side effects may occur, the studies aim to find a treatment that effectively fights cancer with the fewest possible side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for oropharyngeal cancer because they explore new combinations and approaches that could improve patient outcomes. Arm II offers a reduced radiation dose combined with cisplatin, aiming to lessen side effects while maintaining effectiveness. Arm III introduces nivolumab, an immunotherapy drug, which works by boosting the body's immune response to fight cancer cells, paired with reduced radiation. This combination could potentially enhance cancer control while minimizing the harsh side effects often seen with traditional treatments like high-dose radiation and cisplatin. By integrating immunotherapy, researchers hope to achieve better cancer targeting and longer-lasting effects.

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

Research has shown that for patients with HPV-positive throat cancer, reducing the radiation dose while using cisplatin, as in Arm II of this trial, can still achieve excellent survival rates. Studies have found survival rates exceeding 96% with this approach, which is very encouraging. Less radiation is believed to cause fewer side effects while maintaining effectiveness.

In Arm III of this trial, researchers are testing the combination of reduced radiation with nivolumab, a type of immunotherapy. Early results suggest that nivolumab can help the immune system fight cancer cells effectively. Initial data indicate that using nivolumab with a lower radiation dose might also work well and reduce side effects. Both treatment options in this trial appear promising for effectively treating early-stage HPV-positive throat cancer. ^{2 6 7 8 9}

Who Is on the Research Team?

Sue S Yom

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

This trial is for adults with early-stage, HPV-positive oropharyngeal cancer not linked to smoking. Participants must have a specific type of squamous cell carcinoma, limited smoking history (no more than 10 pack-years), and meet certain health criteria including blood counts and organ function. Those with prior invasive malignancies within 3 years, previous immune therapy, severe allergies to monoclonal antibodies or cisplatin, active autoimmune diseases requiring treatment, or pregnant/nursing women are excluded.

Inclusion Criteria

Clinical stage T1-2, N1, M0 or T3, N0-N1, M0

Pathologically proven diagnosis of squamous cell carcinoma of the oropharynx

Clinically or radiographically evident measurable disease at the primary site or at nodal stations

Exclusion Criteria

Radiographically matted nodes

Supraclavicular nodes

Simultaneous primary cancers or separate bilateral primary tumor sites

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients undergo radiation therapy and receive either cisplatin or nivolumab based on randomization. Treatment continues for 6 weeks.

6 weeks

Weekly visits for radiation therapy

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up includes imaging and assessments.

12-14 weeks initially, then every 3 months for 2 years, every 6 months for 3 years, and annually thereafter

Regular follow-up visits

Long-term Follow-up

Participants continue to be monitored for progression-free survival and overall survival.

Up to 6 years

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Image Guided Radiation Therapy
• Intensity-Modulated Radiation Therapy
• Nivolumab

Trial Overview The study compares the effectiveness of reduced radiation therapy combined with nivolumab (an immunotherapy drug) versus standard radiation therapy paired with cisplatin (a chemotherapy drug). The goal is to see if lower doses of radiation can be as effective when used alongside newer treatments like nivolumab in non-smoking related throat cancer caused by HPV.

How Is the Trial Designed?

Group I: Arm III (Reduced RT + nivolumab) Experimental Treatment 10 Interventions

Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.

Group II: Arm II (Reduced RT + cisplatin) Experimental Treatment 11 Interventions

Patients undergo reduced dose RT as 60 Gy IMRT or IGRT QD over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.

Group III: Arm I (Standard RT + cisplatin) Active Control 11 Interventions

Patients undergo standard dose RT as 70 Gy IMRT or IGRT over 6 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.

Cisplatin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Published Research Related to This Trial

In a phase II clinical trial involving 114 patients with HPV-associated oropharyngeal cancer, a de-intensified treatment regimen of 60 Gy radiotherapy and low-dose cisplatin resulted in excellent 2-year outcomes: 95% local-regional control and 86% progression-free survival.

The study found that this treatment approach minimized the need for chemotherapy and surgery, with no severe late adverse events reported, indicating a safer and effective option for patients with minimal smoking history.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Trial of De-Intensified Chemoradiotherapy for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma. Chera, BS., Amdur, RJ., Green, R., et al.[2021]

Intensity-modulated radiotherapy (IMRT) for oropharyngeal squamous cell carcinoma showed promising 5-year local control rates, with 87% overall and varying by cancer stage, indicating its efficacy in managing advanced disease.

The treatment resulted in a 5-year cause-specific survival rate of 85% and an overall survival rate of 76%, with a relatively low incidence of severe late complications (8%), suggesting that IMRT is a safe and effective option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensity-modulated radiotherapy for oropharyngeal squamous cell carcinoma. Mendenhall, WM., Amdur, RJ., Morris, CG., et al.[2022]

In a subgroup analysis of 33 patients with HPV-related oropharyngeal cancer, treatment with cisplatin (CDDP) showed a trend towards better locoregional control and overall survival compared to cetuximab (CTX), suggesting that CDDP may be a more effective first-line treatment for these patients.

Serious or fatal infectious complications were only observed in the CTX treatment group, indicating potential safety concerns associated with cetuximab in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subgroup Analysis According to Human Papillomavirus Status and Tumor Site of a Randomized Phase II Trial Comparing Cetuximab and Cisplatin Combined With Radiation Therapy for Locally Advanced Head and Neck Cancer. Buglione, M., Maddalo, M., Corvò, R., et al.[2018]

In a study of 10 patients with head and neck squamous cell carcinoma treated with intensity-modulated radiotherapy (IMRT), no patients experienced death or loco-regional relapse, indicating promising efficacy of the treatment.

The study found that limiting the radiation dose to the contralateral parotid gland was more achievable with a maximum IMRT dose of 50 Gy, resulting in lower acute toxicity and a 50% rate of grade 0-1 late xerostomia at 3 months, suggesting potential for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Intensity-modulated radiation therapy for head and neck cancers with bilateral irradiation of the neck : preliminary results]. Lapeyre, M., Marchesi, V., Mege, A., et al.[2018]

In a study of 160 patients with advanced oropharyngeal squamous cell carcinoma treated with carboplatin, paclitaxel, and radiation over 10 years, the overall survival rates were 81.7% at 3 years and 70.7% at 5 years, indicating effective treatment outcomes.

The treatment demonstrated an acceptable side effect profile, with the most common adverse effect being acute dysphagia (75.25%), and only 11.9% of patients experiencing significant hematologic toxicities, suggesting carboplatin may be a safer alternative to cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival outcomes in patients with oropharyngeal cancer treated with carboplatin/paclitaxel and concurrent radiotherapy. Roskies, M., Kay-Rivest, E., Mascarella, MA., et al.[2018]

Patients with locally advanced oropharyngeal squamous cell carcinoma who received cisplatin (CDDP) had a significantly better 2-year overall survival rate compared to those treated with cetuximab (CTX), with a hazard ratio of 1.68 indicating higher mortality for CTX users.

Cisplatin also resulted in lower overall treatment costs compared to CTX and carboplatin, despite higher rates of antiemetic use and hospital visits for side effects, suggesting it may be a more cost-effective option for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing outcomes of concurrent chemotherapy regimens in patients 65 years old or older with locally advanced oropharyngeal carcinoma. Amini, A., Eguchi, M., Jones, BL., et al.[2023]

In a study of 421 patients with HPV-associated oropharyngeal squamous cell carcinoma, high-dose cisplatin (HDC) showed better outcomes for stage III disease, including lower rates of locoregional recurrence and distant metastasis, as well as improved overall survival compared to triweekly carboplatin (TC).

However, HDC was associated with significantly higher toxicity, including increased rates of severe leukopenia and weight loss, suggesting that TC may be a safer option for patients with early-stage disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triweekly carboplatin as a potential de-intensification agent in concurrent chemoradiation for early-stage HPV-associated oropharyngeal cancer. Iganej, S., Beard, BW., Chen, J., et al.[2020]

In a study of 60 patients with locally advanced head and neck squamous cell carcinoma (HNSCC), weekly low-dose cisplatin (30 mg/m2) resulted in significantly lower acute toxicities compared to high-dose cisplatin (100 mg/m2 every 3 weeks), with 56.6% of patients experiencing severe side effects versus 76.6% in the high-dose group.

While the low-dose regimen had better patient compliance (70% completing at least 6 doses) and lower toxicity, it also resulted in a lower loco-regional control rate (57.6%) compared to the high-dose group (72.8%), indicating a trade-off between safety and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin Weekly Versus Every 3 Weeks Concurrently with Radiotherapy in the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinomas: What Is the Best Dosing and Schedule? Mashhour, K., Hashem, W.[2020]

Citations

1. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2788326

Elective Radiotherapy Dose and Field in HPV-Associated ... Several clinical trials have shown that in patients with select HPV-positive OPC, radiation dose to gross disease can be safely reduced, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8778604/

Evaluation of Substantial Reduction in Elective ... Reduction of radiotherapy dose and target volume to subclinical regions may achieve good clinical outcomes with favorable patient quality of ...

3. nrgoncology.org nrgoncology.org/Home/News/Post/reduced-dose-radiation-with-cisplatin-improves-outcomes-for-hpv-associated-oropharyngeal-carcinoma-patients-on-nrg-oncology-study-justifies-phase-iii-trial

Reduced-Dose Radiation with Cisplatin Improves Outcomes f 2-year overall survival rates were 96.7% and 97.3% for the IMRT+C and the IMRT alone arms, respectively. While more grade 3-4 acute toxicities ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03952585

Study Details | NCT03952585 | De-intensified Radiation ... This phase II/III trial studies how well a reduced dose of radiation therapy works with nivolumab compared to cisplatin in treating patients with human ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S036030162307726X

Selective Treatment Deintensification by Reducing ... Selective radiation therapy dose reduction and concurrent chemotherapy removal based on IC response in HPV + OPSCC was feasible and promising.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8078254/

Reduced-Dose Radiation Therapy for HPV-Associated ... Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02254278

Study Details | NCT02254278 | Reduced-Dose Intensity ... This randomized phase II trial studies the side effects and how well modestly reduced-dose intensity-modulated radiation therapy (IMRT) with or without ...

8. ecancer.org ecancer.org/en/news/19552-reduced-dose-rt-with-cisplatin-improves-outcomes-for-hpv-associated-oropharyngeal-carcinoma

Reduced-dose RT with cisplatin improves outcomes for ... 2-year overall survival rates were 96.7% and 97.3% for the IMRT C and the IMRT alone arms, respectively. While more grade 3-4 acute toxicities ...

9. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCT02254278

Reduced-Dose Intensity-Modulated Radiation Therapy ... This randomized phase II trial studies the side effects and how well modestly reduced-dose intensity-modulated radiation therapy (IMRT) with or without ...