Trametinib + Hydroxychloroquine for Pancreatic Cancer

(THREAD Trial)

Not currently recruiting at 1 trial location

Overseen By Susan Sharry

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Utah

Must not be taking: Antineoplastics, Radiotherapy

Disqualifiers: Brain metastases, Retinal vein occlusion, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and understand the side effects of combining trametinib (a cancer treatment drug) and hydroxychloroquine (an antimalarial drug) for treating pancreatic cancer that cannot be surgically removed. Trametinib may inhibit cancer cell growth, while hydroxychloroquine could help kill or prevent the spread of these cells. This combination treatment might outperform existing options for patients with metastatic pancreatic cancer. Individuals with metastatic pancreatic cancer who cannot undergo surgery might be suitable candidates, especially if they have already tried standard treatments. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have received certain cancer treatments or investigational therapies within 2 weeks before starting the study treatment.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the combination of trametinib and hydroxychloroquine is generally well-tolerated by patients with advanced pancreatic cancer. In studies, patients who had already tried many other treatments received this drug pair, and it was usually safe for them. Some side effects occurred, but they were not severe for most people.

Trametinib blocks certain proteins that help cancer cells grow, while hydroxychloroquine, often used in cancer treatment, helps prevent cancer cells from spreading. Although these drugs work in different ways, together they may be more effective against cancer.

In summary, studies with pancreatic cancer patients have shown promising safety results for the combination of trametinib and hydroxychloroquine. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pancreatic cancer?

Most treatments for pancreatic cancer focus on chemotherapy or targeted therapies like gemcitabine and FOLFIRINOX. But this new combination of trametinib and hydroxychloroquine works differently. Trametinib targets a specific pathway called MEK, which is often overactive in cancer cells, while hydroxychloroquine interferes with the cancer cells' ability to clear out waste, potentially leading to cell death. Researchers are excited because this dual action could overcome resistance to current treatments and improve outcomes for patients with this challenging cancer.

What evidence suggests that this treatment might be an effective treatment for pancreatic cancer?

This trial will evaluate the combination of trametinib and hydroxychloroquine for treating pancreatic cancer. Research has shown that this combination might help treat pancreatic cancer. In some studies, patients who took this combination experienced stable cancer for about 2 to 2.8 months, meaning their cancer did not worsen during that time. However, not all studies found this treatment effective, particularly for patients with certain genetic changes. Patients with advanced cancer generally tolerated the treatment well. These findings suggest possible benefits, but the results have been mixed. ^{2 3 6 7 8}

Who Is on the Research Team?

Conan G. Kinsey

Principal Investigator

Huntsman Cancer Institute/ University of Utah

Are You a Good Fit for This Trial?

This trial is for adults with advanced pancreatic cancer that has spread and isn't eligible for surgery. Participants must have tried two standard treatments or refused them, have measurable disease, be able to provide a biopsy, and have functioning major organs. They should not be pregnant, agree to use effective contraception, and not have certain health conditions like active bleeding or recent major surgery.

Inclusion Criteria

I can take care of myself and perform daily activities.

You have enough infection-fighting white blood cells in your body.

I have recovered from previous treatment side effects, or they are minor and stable.

Exclusion Criteria

I had major surgery less than 3 weeks ago or am still dealing with its side effects.

I have not had radiotherapy in the last 2 weeks, except for treating bone metastasis.

I have had a major bleeding event in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive trametinib and hydroxychloroquine orally on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment, including the assessment of adverse events.

30 days after last dose

Long-term follow-up

Participants are assessed for response rate to the treatment over an extended period.

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Hydroxychloroquine
• Trametinib

Trial Overview The study is testing the combination of Trametinib and Hydroxychloroquine in patients with pancreatic cancer. Trametinib blocks enzymes needed for cell growth while Hydroxychloroquine may prevent tumor cells from growing or spreading. The goal is to find the best dose of Hydroxychloroquine that can be given safely with Trametinib.

How Is the Trial Designed?

Group I: Treatment (trametinib, hydroxychloroquine) Experimental Treatment 2 Interventions

Patients receive trametinib PO QD on days 1-28 and hydroxychloroquine PO QD or BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Hydroxychloroquine is already approved in United States, European Union for the following indications:

Approved in United States as Plaquenil for:

• Malaria
• Rheumatoid Arthritis
• Systemic Lupus Erythematosus

Approved in European Union as Plaquenil for:

• Malaria
• Rheumatoid Arthritis
• Systemic Lupus Erythematosus

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Novartis Pharmaceuticals

Industry Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

The combination of gemcitabine and chloroquine was well tolerated in a phase I study involving nine patients with metastatic pancreatic cancer, with no dose-limiting toxicities observed.

Three patients showed a partial response to the treatment, and the median overall survival was 7.6 months, suggesting that this combination may enhance the effectiveness of chemotherapy and warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of a chloroquine-gemcitabine combination in patients with metastatic or unresectable pancreatic cancer. Samaras, P., Tusup, M., Nguyen-Kim, TDL., et al.[2022]

In a study of 35 patients with high-risk pancreatic adenocarcinoma, preoperative treatment with hydroxychloroquine and gemcitabine led to a median overall survival of 31 months, with 31% of patients surviving beyond 5 years, indicating promising long-term outcomes.

The treatment resulted in a significant reduction in serum CA19-9 levels and a partial treatment response in 48% of patients, suggesting that this combination therapy is effective in managing pancreatic cancer and improving surgical resection rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encouraging long-term survival following autophagy inhibition using neoadjuvant hydroxychloroquine and gemcitabine for high-risk patients with resectable pancreatic carcinoma. AlMasri, SS., Zenati, MS., Desilva, A., et al.[2023]

A 61-year-old woman developed permanent bilateral bull's-eye retinopathy after taking hydroxychloroquine (HCQ) for only 2 months, despite not having known risk factors for retinal toxicity.

This case highlights the need for additional screening tests for HCQ toxicity, as the patient experienced adverse effects even with a lower drug load and without common risk factors, suggesting other underlying mechanisms may contribute to toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Highly Accelerated Onset of Hydroxychloroquine Macular Retinopathy. Stern, EM., Johnson, JS., Mazzulla, DA.[2020]

A 71-year-old woman experienced retinal toxicity after taking hydroxychloroquine for 5 years, highlighting the risk of ocular side effects, particularly toxic maculopathy, associated with this medication.

The only effective treatment for hydroxychloroquine toxicity is to discontinue the drug, but the toxic effects may continue to progress due to the slow clearance of the medication, emphasizing the importance of regular eye examinations before and during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retinal toxicity secondary to Plaquenil therapy. Hanna, B., Holdeman, NR., Tang, RA., et al.[2016]

Hydroxychloroquine sulfate (HCQ) is used to treat autoimmune disorders but can cause severe retinal toxicity, including irreversible maculopathy, necessitating careful monitoring and potential discontinuation of therapy.

It is crucial for healthcare providers, including rheumatologists and ophthalmologists, to be aware of the risks associated with HCQ and to implement screening protocols to minimize the incidence of toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retinal toxicity associated with chronic exposure to hydroxychloroquine and its ocular screening. Review. Geamănu Pancă, A., Popa-Cherecheanu, A., Marinescu, B., et al.[2022]

In a study of 1102 patients with metastatic pancreatic cancer, FOLFIRINOX treatment resulted in a median overall survival of 9.27 months, significantly longer than the 6.87 months observed with gemcitabine plus nab-paclitaxel (P < 0.001).

Patients receiving FOLFIRINOX also experienced 17.3% fewer posttreatment hospitalizations and 20% lower posttreatment costs compared to those treated with gemcitabine plus nab-paclitaxel, indicating better safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of FOLFIRINOX vs Gemcitabine Plus Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma. Klein-Brill, A., Amar-Farkash, S., Lawrence, G., et al.[2023]

A new method was developed to measure both isomers of hydroxychloroquine (HCQ) and its metabolites in plasma and urine, which is crucial for optimizing clinical dosing.

In a preliminary study with four volunteers, after a single 200 mg dose of Plaquenil, the ratio of the two isomers of HCQ remained approximately equal over 8 hours, but the excretion of HCQ and its metabolites showed stereoselective patterns over 48 hours.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of the stereoisomers of hydroxychloroquine and its major metabolites in plasma and urine following a single oral administration of racemic hydroxychloroquine. Iredale, J., Fieger, H., Wainer, IW.[2021]

A 75-year-old woman experienced cenesthetic hallucinations and disorientation after 10 days of hydrochloroquine treatment for erosive plantar lichen planus, highlighting a rare neuropsychiatric side effect of the medication.

The patient's psychiatric symptoms resolved within a month after stopping hydrochloroquine, indicating that these side effects may be idiosyncratic and not related to dosage, which is important for clinicians to consider when prescribing this drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hallucinations during treatment with hydrochloroquine]. Ferraro, V., Mantoux, F., Denis, K., et al.[2019]

In a phase II trial involving 17 patients with advanced pancreatic cancer, the combination of sorafenib and gemcitabine showed no objective responses, with only 18% of patients achieving stable disease.

The treatment resulted in a median overall survival of 4.0 months and was associated with significant toxicities, including thrombosis in 18% of patients, indicating that this combination is not effective for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium. Kindler, HL., Wroblewski, K., Wallace, JA., et al.[2022]

In a study of 62 patients with advanced pancreatic ductal adenocarcinoma (PDAC) who had previously failed gemcitabine treatment, second-line chemotherapy with capecitabine and oxaliplatin (XELOX) showed a partial tumor response in 11.3% of patients and stable disease in 32.3%.

The median progression-free survival was 88 days and overall survival was 158 days, indicating that XELOX can provide a meaningful treatment option for patients with advanced PDAC, although there were notable adverse events including vomiting and one treatment-related death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Capecitabine Plus Oxaliplatin Combination Chemotherapy for Advanced Pancreatic Cancer after Failure of First-Line Gemcitabine-Based Therapy. Chung, KH., Ryu, JK., Son, JH., et al.[2022]

In a phase III trial involving 104 patients with advanced pancreatic cancer, the combination of gemcitabine and sorafenib did not show an improvement in progression-free survival (PFS) compared to gemcitabine alone, with median PFS of 5.7 months for the placebo group versus 3.8 months for the sorafenib group.

Overall survival rates were also similar between the two groups, with median overall survivals of 9.2 months for gemcitabine/placebo and 8 months for gemcitabine/sorafenib, indicating that adding sorafenib does not enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Gonçalves, A., Gilabert, M., François, E., et al.[2023]

In a study of 13 patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) receiving trametinib combined with hydroxychloroquine or CDK4/6 inhibitors, only one patient achieved stable disease, indicating limited efficacy of this treatment regimen.

The median overall survival for patients treated with trametinib plus hydroxychloroquine was 4.2 months, and 4.7 months for those treated with CDK4/6 inhibitors, with 50% of patients experiencing significant adverse events, suggesting safety concerns alongside limited effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world analysis of trametinib in combination with hydroxychloroquine or CDK4/6 inhibitor as third- or later-line therapy in metastatic pancreatic adenocarcinoma. Tang, H., Ge, Y., You, T., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11445348/

Trametinib in combination with hydroxychloroquine or ... Combined treatment with trametinib and palbociclib, together with dabrafenib in two non-PDAC cases, resulted in a clinical benefit rate of 56% ( ...

2. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-023-11464-3

or later-line therapy in metastatic pancreatic adenocarcinoma Moreover, in patients treated with trametinib plus HCQ and a CDK4/6 inhibitor, the median progression-free survival was 2.0 and 2.8 months, ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03825289

Trametinib and Hydroxychloroquine in Treating Patients ... Giving trametinib together with hydroxychloroquine may work better in treating patients with pancreatic cancer. Detailed Description. PRIMARY OBJECTIVES: I. To ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39352477/

data from a retrospective, multicentric cohort (AIO AIO ... Conclusion: THCQ and TP are not effective in patients with advanced PDAC harboring KRAS mutations or alterations in MAPK/CDKN2A/B. Keywords: ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.e16735

Use of a real-world data approach to rapidly generate ... Conclusions: Combinatorial MEK and autophagy inhibition was well tolerated in heavily treated metastatic pancreatic cancer patients. Trametinib/ ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10563303/

or later-line therapy in metastatic pancreatic adenocarcinoma 1). Specifically, in patients treated with trametinib plus HCQ or a CDK4/6 inhibitor, the median PFS was 2.0 and 2.8 months (95% CI: 2.0 ...

7. cancercommons.org cancercommons.org/latest-insights/using-real-world-evidence-to-show-initial-results-of-a-drug-combination-in-pancreatic-cancer-patients/

Using Real World Evidence to Show Initial Results of a ... Cancer Commons presented initial findings from our real-world data registry on a novel treatment combination for pancreatic cancer patients.

8. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/counter/pdf/10.1186/s12885-023-11464-3.pdf?utm_source=consensus

A real-world analysis of trametinib in combination with ... events in 10 patients with available safety data ... pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial ...