Cyclophosphamide + Pembrolizumab for Melanoma

Overseen By Chao Family Comprehensive Cancer Center University of California, Irvine

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, Irvine

Must be taking: PD-1/PD-L1

Must not be taking: Antivirals, Antiretrovirals

Disqualifiers: Ocular melanoma, CNS metastases, others

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: Unknown

Duration: Up to 3 years

14 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that certain treatments like investigational or standard immunotherapy, chemotherapy, or radiation should not be taken within 6-9 weeks of the first dose of the trial therapy. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drugs Cyclophosphamide and Pembrolizumab for treating melanoma?

Research shows that pembrolizumab, one of the drugs in the treatment, improves survival in patients with advanced melanoma and is superior to another drug, ipilimumab, in treating this condition. Additionally, pembrolizumab has shown promising results when used in combination with other treatments for melanoma. ^{1 2 3 4 5}

Is the combination of Cyclophosphamide and Pembrolizumab safe for treating melanoma?

Pembrolizumab is generally well tolerated and has a favorable safety profile in treating advanced melanoma, with common side effects including fatigue, rash, itching, and diarrhea. Less common but more serious side effects can include immune-related issues like hypothyroidism, colitis, hepatitis, and pneumonitis. Cyclophosphamide is not specifically mentioned in the provided research, so its safety in combination with pembrolizumab is not detailed here. ^{6 7 8 9 10}

How is the drug combination of Cyclophosphamide and Pembrolizumab unique for treating melanoma?

This treatment combines Cyclophosphamide, a chemotherapy drug, with Pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells. Pembrolizumab has shown improved survival outcomes in advanced melanoma, and combining it with Cyclophosphamide may enhance its effectiveness by potentially boosting the immune response. ^{1 3 11 12 13}

What is the purpose of this trial?

This is a phase 2, single-arm, open label clinical trial determining efficacy of Cyclophosphamide and Pembrolizumab in subjects with melanoma.

Research Team

Warren Chow, MD

Principal Investigator

Chao Family Comprehensive Cancer Center

Eligibility Criteria

Adults with advanced non-ocular melanoma who've previously had PD-1/PD-L1 therapy can join. They need measurable disease, an ECOG score of 0-2, and a life expectancy over 12 weeks. Participants must have good organ function and agree to contraception. Exclusions include ocular melanoma, severe prior pembrolizumab side effects, untreated brain metastases, certain viral infections, or recent other cancer treatments.

Inclusion Criteria

I agree to use effective birth control during and 3 months after the study.

My cancer can be measured by scans and has grown in previously treated areas.

I can take care of myself and am up and about more than half of my waking hours.

Exclusion Criteria

I have been diagnosed with a type of eye cancer called uveal melanoma.

I stopped a previous cancer treatment due to severe side effects.

My cancer has a B-RAF mutation and I haven't taken, or can't take, BRAF/MEK inhibitors.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Pembrolizumab 200mg IV every 21 days or 400 mg IV every 42 days and Cyclophosphamide 50mg PO daily on days 1-14 every 21 days

Up to 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Cyclophosphamide
• Pembrolizumab

Trial Overview This phase 2 trial tests Cyclophosphamide combined with Pembrolizumab in patients whose melanoma didn't respond to checkpoint inhibitors. It's open-label so everyone knows what treatment they're getting and aims to see how effective this combination is.

Participant Groups

Group I: Pembrolizumab + Cyclophosphamide Experimental Treatment 2 Interventions

Pembrolizumab 200mg IV every 21 days or 400 mg IV every 42 days Cyclophosphamide 50mg PO daily on days 1-14 every 21 days for melanoma patients

Who Is Running the Clinical Trial?

University of California, Irvine

Lead Sponsor

Trials

580

Recruited

4,943,000+

Findings from Research

In a study of 183 patients with advanced melanoma treated with pembrolizumab, several baseline factors such as active brain metastases, higher total metabolic tumor volume (TMTV), and lower absolute lymphocyte count (ALC) were linked to worse survival outcomes.

TMTV was identified as a more effective predictor of treatment futility compared to other markers like C-reactive protein (CRP) and lactate dehydrogenase (LDH), suggesting that patients with high TMTV may not benefit from pembrolizumab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Comprehensive Analysis of Baseline Clinical Characteristics and Biomarkers Associated with Outcome in Advanced Melanoma Patients Treated with Pembrolizumab. Awada, G., Jansen, Y., Schwarze, JK., et al.[2021]

In a phase 3 trial involving 706 patients with unresectable stage III or IV melanoma, the combination of epacadostat and pembrolizumab did not show any significant improvement in progression-free survival or overall survival compared to pembrolizumab alone.

The most common serious side effects were similar between the two groups, with no treatment-related deaths reported, indicating that the combination therapy was generally safe but ineffective in enhancing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Long, GV., Dummer, R., Hamid, O., et al.[2020]

In a study of 67 advanced melanoma patients treated with pembrolizumab, the drug demonstrated a 27% overall response rate, with 6.5% achieving complete responses, indicating its efficacy even in heavily pretreated patients.

The median overall survival for cutaneous melanoma patients was 14 months, with an 18-month survival rate of 47.1%, and importantly, there were no serious adverse events reported, highlighting the safety of pembrolizumab in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program. González-Cao, M., Arance, A., Piulats, JM., et al.[2018]

In a study of 84 advanced melanoma patients who had previously failed anti-PD-1 therapy, ipilimumab alone showed a 16% overall response rate, while the combination of ipilimumab and nivolumab had a slightly higher response rate of 21%.

Despite the combination therapy showing a higher response rate, both treatments had similar one-year overall survival rates of around 54-55%, suggesting that ipilimumab alone remains a viable option for patients who did not respond to prior anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma. Zimmer, L., Apuri, S., Eroglu, Z., et al.[2021]

In a randomized trial comparing FDA-approved immune checkpoint inhibitors for advanced melanoma, pembrolizumab showed significantly better treatment outcomes than ipilimumab.

This study is notable as it is the first to directly compare these two therapies as first-line treatments, highlighting pembrolizumab's potential as a more effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab superior to ipilimumab in melanoma. [2017]

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

In a study of 88 advanced melanoma patients treated with pembrolizumab, 81.8% experienced any-grade toxicities, with skin and gastrointestinal issues being the most common side effects.

Despite the high incidence of side effects, pembrolizumab was found to be well tolerated in real-world settings, and severe toxicities were manageable with systemic steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK. So, AC., Board, RE.[2022]

A patient with metastatic melanoma developed rare complications of epididymo-orchitis and encephalitis after receiving pembrolizumab, highlighting the potential for serious immune-related adverse events from immune checkpoint inhibitors.

The patient's condition improved rapidly with high-dose corticosteroids, suggesting that severe cases of epididymo-orchitis related to anti-PD-1 therapy can be effectively treated with this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe Epididymo-Orchitis and Encephalitis Complicating Anti-PD-1 Therapy. Quach, HT., Robbins, CJ., Balko, JM., et al.[2023]

A 45-year-old male with metastatic melanoma experienced severe immune-related adverse events from ipilimumab, leading to its discontinuation, but successfully transitioned to pembrolizumab.

After over 20 months of treatment with pembrolizumab, the patient has shown no major toxicities and has achieved an ongoing partial response, suggesting that pembrolizumab may be a safe and effective option for patients with prior severe adverse events from other immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in a BRAF-mutant metastatic melanoma patient following a severe immune-related adverse event with ipilimumab. Aya, F., Fernández-Martínez, A., Gaba, L., et al.[2017]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

Pembrolizumab, along with other immunotherapy drugs, showed significant improvements in treatment outcomes for advanced melanoma, but none were found to be cost-effective in Iran based on a cost-effectiveness threshold of $3,532.

For Pembrolizumab and other immunotherapy options to be considered cost-effective, their prices would need to be reduced by over 90%, highlighting a significant barrier to access for these potentially life-saving treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-utility analysis of Pembrolizumab compared to other alternative immunotherapy and chemotherapy treatments for patients with advanced melanoma in Iran. Bashari, N., Safaei Lari, M., Darvishi, A., et al.[2023]

Pembrolizumab, an immune checkpoint inhibitor, has significantly improved survival rates and response rates in patients with advanced melanoma compared to standard therapies.

The drug has a good safety profile and is currently being tested in combination therapies and adjuvant settings, which may further enhance treatment outcomes for melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Challenging the standard of care in advanced melanoma: focus on pembrolizumab. Abdul-Karim, RM., Cowey, CL.[2020]

Pembrolizumab (PEM) significantly improved short-term treatment effectiveness and long-term survival rates in patients with advanced cutaneous malignant melanoma compared to chemotherapy with Temozolomide, with a notable increase in one-year survival rates (53.85% vs. 40.00%).

The use of PEM did not lead to a higher incidence of adverse reactions compared to the control group, indicating that it is a relatively safe treatment option for patients with this type of melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical application effect of Pembrolizumab in the treatment of advanced cutaneous malignant melanoma. Fu, L., Zhang, H., Jiang, J., et al.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

A Comprehensive Analysis of Baseline Clinical Characteristics and Biomarkers Associated with Outcome in Advanced Melanoma Patients Treated with Pembrolizumab. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. [2020]

3. Italy pubmed.ncbi.nlm.nih.gov

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma. [2021]

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

Pembrolizumab superior to ipilimumab in melanoma. [2017]

6. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Severe Epididymo-Orchitis and Encephalitis Complicating Anti-PD-1 Therapy. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in a BRAF-mutant metastatic melanoma patient following a severe immune-related adverse event with ipilimumab. [2017]

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Cost-utility analysis of Pembrolizumab compared to other alternative immunotherapy and chemotherapy treatments for patients with advanced melanoma in Iran. [2023]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Challenging the standard of care in advanced melanoma: focus on pembrolizumab. [2020]

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

Clinical application effect of Pembrolizumab in the treatment of advanced cutaneous malignant melanoma. [2021]