ctDNA-Guided Therapy for Lung Cancer

(ctDNA Lung RCT Trial)

Overseen By Natasha Leighl, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: Immunosuppressants, Anticancer therapies

Disqualifiers: Active autoimmune disorders, Uncontrolled HIV, Recent myocardial infarction, others

Stay on Your Current Meds You can continue your current medications while participating

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: 4

Duration: 12 weeks

66 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a blood test for circulating tumor DNA (ctDNA) can guide additional treatment, such as chemo-immunotherapy, after lung cancer surgery to prevent recurrence. Participants will either receive a combination of drugs, including Pemetrexed or Gemcitabine with Cisplatin or Carboplatin, and Nivolumab, or undergo regular ctDNA testing. This study suits individuals who have had a complete surgical removal of non-small cell lung cancer (NSCLC) and have not received chemotherapy or radiation for this diagnosis. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to the development of potentially effective therapies.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received any conventional or investigational anticancer therapy within 21 days or radiotherapy within 14 days before starting the study treatment.

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

Research has shown that pemetrexed is generally safe and often preferred due to fewer side effects compared to other cancer drugs, particularly for non-squamous non-small cell lung cancer. While it can lower white blood cell counts, increasing infection risk, most patients tolerate it well.

Studies indicate that gemcitabine is not overly harsh for most individuals and can be safely combined with other lung cancer treatments without causing significant issues.

Research has demonstrated that cisplatin can improve survival rates in lung cancer patients when used post-surgery. It is a common choice, but like many cancer drugs, it can have side effects, so doctors closely monitor patients.

Carboplatin serves as an alternative for those who do not tolerate cisplatin well. Although detailed real-world safety data is limited, it is generally considered manageable in terms of side effects.

Nivolumab, an FDA-approved immunotherapy for lung cancer, has real-world studies supporting its safety. However, some patients might experience serious side effects, such as pneumonia or breathing problems.

Overall, these treatments are generally well-tolerated in lung cancer patients. While individual experiences may vary, these drugs are used because their benefits typically outweigh the risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it uses a cutting-edge approach called ctDNA-guided therapy to tackle lung cancer. Unlike traditional treatments, which rely heavily on imaging and biopsies, this method involves a simple blood test to detect cancer DNA circulating in the blood. This could potentially allow for more personalized and timely adjustments in treatment, improving effectiveness and reducing unnecessary side effects. Additionally, combining chemotherapy with immunotherapy drugs like Nivolumab might enhance the body's own immune response against cancer cells, offering a promising new strategy for patients.

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

Research has shown that several treatments in this trial have potential for treating non-small cell lung cancer (NSCLC). Participants in the adjuvant chemo-immunotherapy arm may receive Pemetrexed, which has proven effective for various stages of non-squamous NSCLC, extending patient survival and delaying cancer progression. Alternatively, Gemcitabine is an option for advanced NSCLC, increasing survival times. Chemotherapy with Cisplatin, also part of this arm, has improved survival rates for lung cancer patients post-surgery. If Cisplatin is not tolerated, Carboplatin may be given instead, as it has demonstrated benefits in treating NSCLC, often with fewer side effects. Nivolumab, an immunotherapy drug included in this arm, has led to lasting responses and improved survival in advanced NSCLC cases. These findings strongly support using these treatments in the study. ^{1 3 6 7 8}

Who Is on the Research Team?

Natasha Leighl, M.D.

Principal Investigator

Princess Margaret Cancer Centre

Are You a Good Fit for This Trial?

This trial is for adults over 18 with a specific type of lung cancer (NSCLC) that's been surgically removed. They must have detectable ctDNA, good organ function, and no prior chemo or radiotherapy for this cancer. Participants need to use effective contraception and not be pregnant or breastfeeding. Those with other recent cancers, certain infections like HIV, autoimmune diseases, or who've had recent major surgery can't join.

Inclusion Criteria

My organs and bone marrow are functioning well.

My lung cancer type is eligible and lacks targeted treatment options.

I am using effective birth control and will take a pregnancy test before starting treatment.

Exclusion Criteria

I have not received any immune therapy for cancer, such as drugs targeting CTLA-4, PD-1, or PD-L1.

I haven't had cancer treatment or radiotherapy in the last 3 weeks.

I haven't had active autoimmune disorders in the last 3 years, except for allowed conditions like vitiligo, alopecia, stable hypothyroidism, psoriasis not needing systemic treatment, a skin condition not needing systemic therapy, or celiac disease controlled by diet.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive adjuvant chemo-immunotherapy or are observed, with ctDNA testing conducted

12 weeks

4 visits (in-person) for treatment cycles

Follow-up

Participants are monitored for safety, tolerability, and overall survival every 3 months

3 years

Quarterly visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Cisplatin
• ctDNA blood test
• Gemcitabine
• Nivolumab
• Pemetrexed

Trial Overview The study tests if checking for ctDNA in the blood after lung cancer surgery can guide adjuvant therapy to prevent cancer recurrence. It involves drugs like Gemcitabine, Cisplatin, Carboplatin, Nivolumab, Pemetrexed alongside the ctDNA blood test.

How Is the Trial Designed?

Group I: Observation Experimental Treatment 1 Intervention

All participants will have blood taken for ctDNA testing. Participants will be followed as per standard of care every 3 months.

Group II: Adjuvant chemo-immunotherapy therapy Experimental Treatment 6 Interventions

All participants will have blood taken for ctDNA testing. A cycle is 21 days. Pemetrexed (for participants with non-squamous non-small cell lung cancer), intravenously (by vein) on Day 1 of Cycles 1-4, OR gemcitabine (for all other participants) on Days 1 and 8 of Cycles 1-4. Cisplatin\*, intravenously (by vein) on Day 1 of Cycles 1-4 Nivolumab, intravenously (by vein) on Day 1 of Cycles 1-4 \*If cisplatin is not tolerated, carboplatin may be given instead

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

The combination of carboplatin and pemetrexed in 80 patients with advanced non-small cell lung cancer resulted in a 42.5% overall response rate and a disease control rate of 77.5%, indicating effective treatment outcomes.

The treatment was generally well-tolerated, with neutropenia being the only significant adverse event occurring in 7.5% of patients, and no genetic markers were found to predict treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin plus pemetrexed for platinum-pretreated, advanced non-small cell lung cancer: a retrospective study with pharmacogenetic evaluation. Metro, G., Chiari, R., Mare, M., et al.[2015]

In a randomized phase II trial involving 78 patients with extensive-stage small-cell lung cancer (ES-SCLC), the combination of pemetrexed with carboplatin showed a median survival time of 10.4 months and a response rate of 39.5%, indicating it is an effective treatment option.

Both pemetrexed/cisplatin and pemetrexed/carboplatin combinations were well-tolerated, with manageable hematologic toxicities, suggesting that these treatments can be safely administered as first-line therapy for ES-SCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of pemetrexed combined with either cisplatin or carboplatin in untreated extensive-stage small-cell lung cancer. Socinski, MA., Weissman, C., Hart, LL., et al.[2015]

The combination of paclitaxel and carboplatin has shown promising results in treating advanced non-small-cell lung cancer (NSCLC), with reported 1-year survival rates as high as 54%, making it a widely used regimen in clinical practice.

This combination therapy has been effective without additional toxicity, allowing for full doses of both drugs to be administered, and is currently being evaluated in ongoing studies for earlier stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel/carboplatin in the treatment of non-small-cell lung cancer. Belani, CP.[2015]

Carboplatin (CBDCA) has shown similar effectiveness to cisplatin in treating various cancers, including head and neck and ovarian cancers, while demonstrating significantly lower toxicity, particularly in terms of renal effects and side effects like nausea and vomiting.

In clinical trials, carboplatin's dose-limiting factor was myelosuppression, making it a safer alternative to cisplatin, which has more severe side effects, thus positioning carboplatin as a valuable option in cancer chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Development of carboplatin]. Tsukagoshi, S.[2013]

In a phase II study involving 39 patients with completely resected stage II or III non-small cell lung cancer, 92.3% completed four cycles of adjuvant chemotherapy with nedaplatin and irinotecan, indicating high tolerability of this regimen.

The treatment resulted in a median disease-free survival of 49.4 months and a 5-year overall survival rate of 69.8%, suggesting that nedaplatin and irinotecan are effective options for improving outcomes in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of nedaplatin and irinotecan as adjuvant chemotherapy for completely resected non-small cell lung cancer. Murakami, S., Saito, H., Kondo, T., et al.[2019]

In a phase III trial comparing pemetrexed-carboplatin (PC) and etoposide-carboplatin (EC) for extensive-stage small-cell lung cancer, no immunohistochemistry biomarkers were found to predict patient outcomes, leading to the trial's closure for futility.

However, certain single-nucleotide polymorphisms (SNPs) related to genes like SLC19A1 and FPGS showed associations with overall survival, indicating that genetic factors may influence treatment outcomes, but they did not favor one treatment over the other.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer. Smit, EF., Socinski, MA., Mullaney, BP., et al.[2020]

The combination of gemcitabine and pemetrexed showed promising efficacy in treating non-small cell lung cancer (NSCLC), with a median overall survival of 10.1 months and a 1-year survival rate of 42.6% among 60 patients studied.

This cisplatin-free regimen was well-tolerated, with no treatment-related deaths, although some patients experienced significant toxicities like neutropenia and fatigue, indicating it may be a safer alternative for patients unsuitable for cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of pemetrexed-gemcitabine combination in patients with advanced-stage non-small cell lung cancer. Monnerat, C., Le Chevalier, T., Kelly, K., et al.[2022]

Cisplatin (CDDP) has been a key treatment for various cancers since 1972, but its use is limited by significant toxicities, particularly renal impairment.

Carboplatin (CBDCA), a second-generation analogue of cisplatin, has shown reduced renal toxicity and is effective against advanced cancers, although it can cause myelosuppression, particularly affecting platelet counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Second-generation cisplatin analogs]. Ariyoshi, Y., Ota, K.[2013]

In a study involving 10 patients with malignant pleural effusion, the combination of intrapleural cisplatin (DDP) and carboplatin (CBDCA) demonstrated a significant local pharmacological advantage, with high pleural-plasma ratios indicating effective drug delivery to the targeted area.

The treatment was well tolerated, with only mild side effects reported, and showed promising results with six patients achieving complete response and no recurrence of pleural effusion, suggesting that this combination therapy could be a safe and effective option for managing malignant effusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and cisplatin pharmacokinetics after intrapleural combination treatment in patients with malignant pleural effusion. Lerza, R., Vannozzi, MO., Tolino, G., et al.[2020]

Cisplatin is a highly effective cancer treatment that works by causing DNA-DNA cross-links, but it is also highly mutagenic and carcinogenic, leading to variability in response due to different cellular DNA repair capacities.

Carboplatin, a less toxic analogue of cisplatin, has a similar mechanism of action and mutagenic potential, while newer analogues in clinical trials may offer different DNA repair responses, which could influence their effectiveness and resistance development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mutagenic and carcinogenic properties of platinum-based anticancer drugs. Sanderson, BJ., Ferguson, LR., Denny, WA.[2019]

A systematic review of 45 studies involving 16,141 cases found that various platinum-based chemotherapy regimens for incurable non-small cell lung cancer (NSCLC) did not show significant differences in overall survival rates, indicating that multiple regimens can be considered effective.

Specifically, regimens like Carboplatin plus Paclitaxel and Bevacizumab were used as a common comparator, and other combinations such as Cisplatin plus Tegafur gimeracil oteracil and Carboplatin plus S1 were also found to be acceptable first-choice treatments without significantly poorer survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The best platinum regimens for chemo-naive incurable non-small cell lung cancer: network meta-analysis. Horita, N., Nagashima, A., Nakashima, K., et al.[2022]

In a study involving 1669 patients with non-small cell lung cancer (NSCLC), treatment with cisplatin and pemetrexed resulted in significantly longer survival without severe drug-related toxicity compared to cisplatin and gemcitabine, indicating a better clinical benefit-to-risk profile.

For patients with non-squamous NSCLC, cisplatin and pemetrexed not only improved survival without grade 3 or 4 toxicity but also showed superior outcomes in terms of survival without grade 4 toxicity, highlighting its effectiveness and tolerability in this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival without toxicity for cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemonaïve patients with advanced non-small cell lung cancer: a risk-benefit analysis of a large phase III study. Scagliotti, GV., Park, K., Patil, S., et al.[2022]

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