Trametinib + Hydroxychloroquine for Pancreatic Cancer

(THREAD Trial)

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

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase I trial studies the sides effects and best dose of hydroxychloroquine when given together with trametinib in treating patients with pancreatic cancer that has spread to nearby tissue, lymph nodes or other places in the body and cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as hydroxychloroquine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving trametinib together with hydroxychloroquine may work better in treating patients with pancreatic cancer.

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.

What safety data exists for Hydroxychloroquine and Trametinib in humans?

Hydroxychloroquine (Plaquenil) has been associated with eye problems, including retinal toxicity, which can affect vision. It can also cause rare neuropsychiatric side effects like hallucinations. ^{1 2 3 4 5}

How is the drug combination of Trametinib and Hydroxychloroquine unique for treating pancreatic cancer?

The combination of Trametinib and Hydroxychloroquine is unique because it targets pancreatic cancer in a novel way by combining a MEK inhibitor (Trametinib) with an autophagy inhibitor (Hydroxychloroquine), and it is being explored as a third-line treatment option when standard treatments are not available. ^{6 7 8 9 10}

What data supports the effectiveness of the drug combination of Trametinib and Hydroxychloroquine for pancreatic cancer?

Preclinical studies have shown promising results for the combination of Trametinib and Hydroxychloroquine in treating pancreatic cancer, although these regimens have not been extensively tested in patients. Additionally, Hydroxychloroquine combined with gemcitabine has been effective in increasing surgery rates and showing positive biomarker responses in pancreatic cancer patients. ^{6 7 10 11 12}

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

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

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 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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. Germany pubmed.ncbi.nlm.nih.gov

Phase I study of a chloroquine-gemcitabine combination in patients with metastatic or unresectable pancreatic cancer. [2022]

2. England 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. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Comparison of FOLFIRINOX vs Gemcitabine Plus Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma. [2023]

4. United States 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. [2023]

5. England 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. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Retinal toxicity secondary to Plaquenil therapy. [2016]

7. United States pubmed.ncbi.nlm.nih.gov

Highly Accelerated Onset of Hydroxychloroquine Macular Retinopathy. [2020]

8. Romania pubmed.ncbi.nlm.nih.gov

Retinal toxicity associated with chronic exposure to hydroxychloroquine and its ocular screening. Review. [2022]

9. United States 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. [2021]

10. France pubmed.ncbi.nlm.nih.gov

[Hallucinations during treatment with hydrochloroquine]. [2019]

11. United States 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. [2022]

12. Korea (South) pubmed.ncbi.nlm.nih.gov

Efficacy of Capecitabine Plus Oxaliplatin Combination Chemotherapy for Advanced Pancreatic Cancer after Failure of First-Line Gemcitabine-Based Therapy. [2022]