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 proposal will investigate the effect of paricalcitol, hydroxychloroquine, and losartan (PHL) combination of 3 stroma-modifying drugs on pancreatic adenocarcinoma and its stroma.

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 the PHL Combination for Pancreatic Cancer safe for humans?

The safety of the PHL Combination, which includes components like Paricalcitol (a form of vitamin D), has been studied in other contexts. High-dose oral calcitriol (a form of vitamin D) was evaluated for safety in patients with advanced pancreatic cancer, and vitamin D analogues have been shown to inhibit cancer cell growth in lab studies, but more research is needed to confirm safety in humans. ^{1 2 3 4 5}

What makes the PHL Combination drug unique for treating pancreatic cancer?

The PHL Combination drug for pancreatic cancer is unique because it combines Paricalcitol, Hydroxychloroquine, and Losartan, which are not standard treatments for this condition. This combination may offer a novel approach by potentially targeting cancer cells through different mechanisms, such as immune modulation and blood pressure regulation, which are not typically addressed in conventional pancreatic cancer therapies. ^{4 5 6 7 8}

What data supports the effectiveness of the drug combination of Paricalcitol, Hydroxychloroquine, and Losartan for pancreatic cancer?

Research suggests that vitamin D analogues, like Paricalcitol, combined with retinoids can significantly inhibit the growth of pancreatic cancer cells in laboratory studies. However, more studies are needed to confirm these effects in patients. ^{1 2 3 4 5}

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

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]

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]

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]

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]

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]

Citations

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

Inhibitory effect of 220-oxa-1,25-dihydroxyvitamin D3 on the proliferation of pancreatic cancer cell lines. [2019]

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

The Role of Common Pharmaceutical Agents on the Prevention and Treatment of Pancreatic Cancer. [2022]

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

Phase II study of calcitriol-enhanced docetaxel in patients with previously untreated metastatic or locally advanced pancreatic cancer. [2018]

4. England 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. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Growth-inhibitory effects of vitamin D analogues and retinoids on human pancreatic cancer cells. [2019]

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

Combined effects of 1,25-dihydroxyvitamin D3 and platinum drugs on the growth of MCF-7 cells. [2013]

7. United States 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. [2021]

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

Pharmacological Ascorbate Enhances Chemotherapies in Pancreatic Ductal Adenocarcinoma. [2023]