PHL Combination for Pancreatic Cancer

Overseen By Ryan Romasko

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Fox Chase Cancer Center

Must not be taking: Hydroxychloroquine, ARBs, ACE inhibitors

Disqualifiers: Metastatic disease, Retinopathy, Hypotension, others

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

Compensation: Varies

Number of Visits: Unknown

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for pancreatic cancer, focusing on a combination of three drugs: paricalcitol, hydroxychloroquine, and losartan. Researchers aim to determine if this combination can more effectively manage pancreatic adenocarcinoma and its surrounding tissue. Eligible participants should have recently diagnosed pancreatic cancer that may be surgically removable and must have completed specific chemotherapy and radiation treatments. As an Early Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including ACE inhibitors, ARBs (angiotensin II receptor blockers), vitamin D, and hydroxychloroquine, before participating. If you are taking any of these, you may need to stop them to join the study.

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

Researchers are investigating how a combination of three drugs—paricalcitol, hydroxychloroquine, and losartan—might affect pancreatic cancer. This study is in the early stages, but some information about the safety of each drug is known.

Paricalcitol is used for other health issues and is generally safe. Hydroxychloroquine is well-known for treating malaria and autoimmune diseases, with a well-documented safety profile. Losartan is a common medication for high blood pressure and has a good safety record.

Although using these drugs together for pancreatic cancer is new, each one is usually well-tolerated when used alone for other conditions. However, like any treatment, risks may exist. Discuss these with a doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the PHL combination treatment for pancreatic cancer because it targets the disease in a novel way. Unlike the standard of care, which often includes chemotherapy and radiation, this combination uses Paricalcitol, Hydroxychloroquine, and Losartan to potentially disrupt cancer cell growth differently. Paricalcitol, a vitamin D analog, may inhibit cancer cell proliferation, while Hydroxychloroquine can interfere with cancer cell survival mechanisms. Losartan, a blood pressure medication, might improve drug delivery to tumors. This multi-pronged approach could offer a new lifeline for patients by targeting the cancer more comprehensively.

What evidence suggests that the PHL combination could be effective for pancreatic cancer?

Research shows that combining paricalcitol, hydroxychloroquine, and losartan, which participants in this trial may receive as part of the PHL treatment arm, may help treat pancreatic cancer. Studies have found that paricalcitol and hydroxychloroquine can alter the area around the tumor, enhancing chemotherapy's effectiveness. They break down the tumor's protective barrier, allowing treatments to work more effectively. Losartan, a drug often used for high blood pressure, might further modify this tissue. Early evidence suggests that this combination could improve outcomes for patients with pancreatic cancer by boosting chemotherapy's effectiveness. ^{1 2 3 5 6}

Who Is on the Research Team?

Sanjay Reddy, MD, FACS

Principal Investigator

Fox Chase Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with newly diagnosed, resectable pancreatic adenocarcinoma. They must have completed or plan to complete a specific chemotherapy regimen and surgery. Participants need normal organ function, not be pregnant or breastfeeding, and agree to use effective birth control. Those with certain heart conditions, severe eye diseases, uncontrolled illnesses, or taking conflicting medications cannot join.

Inclusion Criteria

I am older than 18 years.

Ability to understand and willingness to sign a written informed consent and HIPAA consent document

I have been newly diagnosed with pancreatic cancer.

Exclusion Criteria

History of allergic reactions attributed to compound of similar chemical or biologic composition to the agent(s) used in this study

Atrio-ventricular blockade of 2nd or 3rd degree

A marked baseline prolongation of QT/QTc interval

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Therapy

Participants receive modified FOLFIRINOX chemotherapy followed by chemoradiation

12 weeks

Window of Opportunity Treatment

Participants receive PHL regimen (Paricalcitol, Hydroxychloroquine, Losartan) for stroma modification

4-8 weeks

Regular visits for monitoring and administration

Surgery

Participants undergo surgery for pancreatic cancer

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Neoadjuvant therapy and surgery only
• Paricalcitol, Hydroxychloroquine, Losartan

Trial Overview The study tests the combination of three drugs (Paricalcitol, Hydroxychloroquine, Losartan) on pancreatic cancer compared to standard neoadjuvant therapy followed by surgery alone. The goal is to see if these drugs can modify the tumor environment and improve outcomes.

How Is the Trial Designed?

Group I: PHL (Paricalcitol, Hydroxychloroquine, Losartan) Experimental Treatment 1 Intervention

Paricalcitol 25 mcg IV administered M-W-F Hydroxychloroquine 600 mg PO BID Losartan 50 mg PO daily

Group II: Neoadjuvant therapy and surgery only (Control) Active Control 1 Intervention

Control arm These patients will proceed to surgery at completion of neoadjuvant therapy.

Who Is Running the Clinical Trial?

Fox Chase Cancer Center

Lead Sponsor

Trials

236

Recruited

39,300+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase II study involving 25 patients with non-resectable pancreatic cancer, the combination of high-dose oral calcitriol and docetaxel showed some efficacy, with 12% of patients achieving a partial response and 28% having stable disease.

The median time-to-progression was 15 weeks and overall survival was 24 weeks, indicating that while this treatment may offer some benefits, it does not appear to be more effective than existing treatments like gemcitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of calcitriol-enhanced docetaxel in patients with previously untreated metastatic or locally advanced pancreatic cancer. Blanke, CD., Beer, TM., Todd, K., et al.[2018]

In a phase II study involving 30 patients with unresectable pancreatic adenocarcinoma, the combination of gemcitabine and 13-cis-retinoic acid was well tolerated, with manageable toxicity primarily related to blood cell counts.

Despite the treatment being well tolerated, the study did not show a significant improvement in the response rate, with a median survival of 7.8 months, suggesting that further research with different retinoids may be necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

13-cis-Retinoic acid in combination with gemcitabine in the treatment of locally advanced and metastatic pancreatic cancer--report of a pilot phase II study. Michael, A., Hill, M., Maraveyas, A., et al.[2022]

1,25-dihydroxyvitamin D3 (1,25(OH)2D3) significantly inhibits the growth of MCF-7 breast cancer cells in a dose-dependent manner, with higher concentrations leading to greater inhibition (up to 34.9% at 100 nM).

Combining 1,25(OH)2D3 with platinum-based drugs like carboplatin and cisplatin enhances the growth inhibition of MCF-7 cells, suggesting a potential synergistic effect that could improve treatment outcomes for breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined effects of 1,25-dihydroxyvitamin D3 and platinum drugs on the growth of MCF-7 cells. Cho, YL., Christensen, C., Saunders, DE., et al.[2013]

MART-10, a new analog of vitamin D, is over 100 times more effective than traditional vitamin D in inhibiting the growth of pancreatic cancer cells, showing promise for treating this aggressive disease.

In animal studies, MART-10 significantly reduced tumor growth without causing hypercalcemia or weight loss, suggesting it may be a safer alternative for patients compared to existing vitamin D treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the potential therapeutic role of a new generation of vitamin D analog, MART-10, in human pancreatic cancer cells in vitro and in vivo. Chiang, KC., Yeh, CN., Hsu, JT., et al.[2021]

The new vitamin D3 analogue, 22-oxa-calcitriol, showed significantly greater anti-proliferative effects on pancreatic cancer cell lines compared to calcitriol, particularly in inhibiting the growth of BxPC-3 xenografts in mice without causing hypercalcemia.

Both 22-oxa-calcitriol and calcitriol caused cell cycle arrest in some pancreatic cancer cell lines, but the effectiveness of these treatments was not solely determined by the levels or mutations of the vitamin D receptor, indicating other factors may influence their efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibitory effect of 220-oxa-1,25-dihydroxyvitamin D3 on the proliferation of pancreatic cancer cell lines. Kawa, S., Yoshizawa, K., Tokoo, M., et al.[2019]

Current treatments for pancreatic cancer have only slightly improved survival rates, highlighting the need for new therapeutic strategies.

Common medications like aspirin, metformin, and statins show potential as chemopreventative and chemotherapeutic agents against pancreatic cancer, but existing epidemiological data on their effectiveness remains inconclusive.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of Common Pharmaceutical Agents on the Prevention and Treatment of Pancreatic Cancer. Amin, S., Boffetta, P., Lucas, AL.[2022]

High-dose intravenous vitamin C (P-AscH-) significantly enhances the effectiveness of standard chemotherapy treatments for pancreatic ductal adenocarcinoma (PDAC), reducing cancer cell survival and increasing DNA damage in vitro.

In mouse models, the combination of P-AscH- with the chemotherapy regimen FOLFIRINOX not only slowed tumor growth but also improved overall survival, suggesting that P-AscH- could be a valuable adjuvant therapy in PDAC treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological Ascorbate Enhances Chemotherapies in Pancreatic Ductal Adenocarcinoma. O'Leary, BR., Ruppenkamp, EK., Steers, GJ., et al.[2023]

The combination of the vitamin D analogue EB1089 and all-trans-retinoic acid significantly inhibited the growth of human pancreatic adenocarcinoma cell lines, achieving a 90% reduction in Capan 1 cells and a 70% reduction in Capan 2 cells.

All-trans-retinoic acid alone was effective in reducing growth by 40% in Capan 1 and Capan 2 cells, while EB1089 did not show significant growth inhibition on its own, highlighting the potential for synergistic effects when these compounds are used together.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Growth-inhibitory effects of vitamin D analogues and retinoids on human pancreatic cancer cells. Zugmaier, G., Jäger, R., Grage, B., et al.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41015572/

Paricalcitol and hydroxychloroquine modulates ... Paricalcitol and hydroxychloroquine modulates extracellular matrix and enhance chemotherapy efficacy in pancreatic cancer. Cancer Gene Ther.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04524702

NCT04524702 | Paricalcitol and Hydroxychloroquine in ... This phase II trial investigates how well paricalcitol and hydroxychloroquine work when combined with gemcitabine and nab-paclitaxel in treating patients ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-00069

Paricalcitol, Hydroxychloroquine, and Losartan for the ... This phase I trial tests whether paricalcitol, hydroxychloroquine and losartan work to modify the supportive tissue (stroma) in the pancreas before surgery.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2212492622000574

Effects of chloroquine and hydroxychloroquine on the ... Recent studies are suggesting effective treatment of PDAC patients may require chemotherapy as well as targeting multiple pathways and biochemical processes.

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39730001/

Mechanism of enhancing chemotherapy efficacy in pancreatic ... Previous research reveals the impact of paricalcitol (P) and hydroxychloroquine (H) on altering the lysosomal fusion, decreasing stromal burden, and triggering ...

6. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/343195

PHL Treatment in Pancreatic Cancer This proposal will investigate the effect of paricalcitol, hydroxychloroquine, and losartan (PHL) combination of 3 stroma-modifying drugs on pancreatic ... data ...