SX-682 + Pembrolizumab for Melanoma

Recruiting at 5 trial locations

Overseen By Stuart Kahn

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Syntrix Biosystems, Inc.

Must not be taking: QT prolonging drugs

Disqualifiers: Active autoimmune disease, Active pneumonitis, Active heart disease, others

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

Compensation: Varies

Number of Visits: 2

77 Participants Needed

Trial Summary

What is the purpose of this trial?

Cancers attract myeloid-derived suppressor cells (MDSCs) that prevent our own immune responses from destroying the cancer. This study will be the first study to begin to determine if the newly discovered drug SX-682 can block cancers from attracting MDSCs. This first study will enroll participants with melanoma, as melanoma cancer has been shown to be able to attract MDSCs. The study will begin to determine if SX-682 is a safe and effective treatment of melanoma. It is thought that SX-682 will block MDSCs from going to the cancer, and thus will allow a patient's own immune system to attack the cancer. The first participants enrolled in the study will receive for 21 days SX-682 as monotherapy. After 21 days participants will receive pembrolizumab therapy (an approved immunotherapy for melanoma) in combination with SX-682 for up to approximately 2 years. Once the safe dose level of SX-682 in combination with pembrolizumab is determined, the remaining participants will be enrolled at the highest safe dose level of SX-682, in combination with pembrolizumab. These participants will receive the combination therapy and be evaluated in the study for approximately 2 years.

Will I have to stop taking my current medications?

The trial requires that you stop taking any QT prolonging drugs (medications that can affect heart rhythm) at least two weeks before starting SX-682 and throughout the trial, unless no alternative is available and the drug is absolutely necessary. If this applies to you, discuss with the trial team for further guidance.

What data supports the effectiveness of the drug Pembrolizumab for melanoma?

Research shows that Pembrolizumab is effective in treating advanced melanoma, with better outcomes compared to another drug, ipilimumab. It has been approved for use in advanced melanoma and has been shown to improve survival rates in patients. ^{1 2 3 4 5}

Is the combination of SX-682 and Pembrolizumab safe for humans?

Pembrolizumab, also known as KEYTRUDA, has been shown to be generally safe in humans, with common side effects including tiredness, rash, itching, and diarrhea. Some less common but serious side effects can include inflammation of the thyroid, colon, liver, and lungs. More studies are needed to fully understand the safety of combining it with SX-682. ^{6 7 8 9 10}

What makes the drug SX-682 + Pembrolizumab unique for treating melanoma?

SX-682 combined with Pembrolizumab is unique because it pairs a novel investigational drug, SX-682, with Pembrolizumab, an established immunotherapy that blocks the PD-1 pathway to enhance the immune system's ability to fight melanoma. This combination may offer a new approach by potentially enhancing the effectiveness of Pembrolizumab through the additional action of SX-682, although specific details about SX-682's mechanism are not provided in the available research. ^{4 10 11 12 13}

Research Team

Stuart Kahn, M.D.

Principal Investigator

Syntrix Biosystems

Eligibility Criteria

Adults over 18 with advanced melanoma that has worsened after anti-PD1 therapy can join. They must understand the study, agree to follow its rules, and have a life expectancy over 12 weeks. Women who can get pregnant and men with partners who can must use contraception. People with certain health conditions or treatments are excluded.

Inclusion Criteria

My condition worsened after anti-PD1 therapy without severe side effects.

Subjects must provide a signed and dated IRB/IEC approved written informed consent form (ICF) in accordance with regulatory and institutional guidelines.

The ICF and HIPAA authorization must be obtained before conducting any procedures that do not form a part of the subject's normal care.

Exclusion Criteria

I have tested positive for HIV/AIDS.

History of allergy to study drug components.

History of severe hypersensitivity reaction to any monoclonal antibody.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monotherapy

Participants receive escalating doses of SX-682 as monotherapy to determine the maximum tolerated dose

3 weeks

Daily visits for dose escalation monitoring

Combination Therapy

Participants receive SX-682 in combination with pembrolizumab in 6-week cycles

Up to 2 years

2 visits per cycle (in-person for pembrolizumab infusions)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Regular follow-up visits

Treatment Details

Interventions

• Pembrolizumab
• SX-682

Trial Overview The trial is testing SX-682's ability to block cells that shield cancer from our immune system in patients with metastatic melanoma, alongside pembrolizumab (an approved treatment). Initially, SX-682 alone is given for 21 days followed by up to two years of combined treatment.

Participant Groups

Group I: Monotherapy: SX-682 dose escalation Experimental Treatment 1 Intervention

Escalating oral doses of SX-682 (study drug) of 25, 50, 100, 200 and 400 mg twice-daily (i.e., 50, 100, 200, 400 and 800 mg total each day.

Group II: Combination therapy: SX-682 dose escalation with pembrolizumab Experimental Treatment 2 Interventions

SX-682 will be administrated at the same dose the participant was administered in monotherapy and will be administered in a 6 week cycle that includes 2 i.v. infusions of pembrolizumab on days 1 and 22 of each cycle, for a total of up to 17 cycles. Once the highest safe dose of SX-682 in combination therapy with pembrolizumab is determined, participants will be enrolled in an expansion phase at that SX-682 dose with pembrolizumab combination therapy.

Who Is Running the Clinical Trial?

Syntrix Biosystems, Inc.

Lead Sponsor

Trials

14

Recruited

810+

University of Miami

Collaborator

Trials

976

Recruited

423,000+

Mayo Clinic

Collaborator

Trials

3,427

Recruited

3,221,000+

Dana-Farber Cancer Institute

Collaborator

Trials

1,128

Recruited

382,000+

Massachusetts General Hospital

Collaborator

Trials

3,066

Recruited

13,430,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

M.D. Anderson Cancer Center

Collaborator

Trials

3,107

Recruited

1,813,000+

University of Rochester

Collaborator

Trials

883

Recruited

555,000+

Findings from Research

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]

In a study of 616 melanoma patients treated with pembrolizumab, specific baseline factors such as high relative eosinophil count, high relative lymphocyte count, low lactate dehydrogenase levels, and limited metastasis were linked to significantly better overall survival rates.

Patients with all four favorable factors had a one-year overall survival probability of 83.9%, while those with none had only 14.7%, highlighting the importance of these biomarkers in predicting treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab. Weide, B., Martens, A., Hassel, JC., et al.[2022]

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]

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]

In a phase 3 trial involving 1,019 patients with resected high-risk stage III melanoma, pembrolizumab significantly improved recurrence-free survival compared to placebo, with a 1-year rate of 75.4% versus 61.0%.

While pembrolizumab was effective, it was associated with a higher rate of severe adverse events (14.7% vs. 3.4% in the placebo group), including one treatment-related death, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. Eggermont, AMM., Blank, CU., Mandala, M., et al.[2022]

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]

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]

The study confirms that PD-1 inhibitors like Pembrolizumab and Nivolumab improve response and survival rates in advanced melanoma patients, especially when combined with the CTLA-4 inhibitor Ipilimumab, which shows superior efficacy compared to monotherapies.

However, these immunotherapies are associated with significant immune-related adverse events, some of which can be life-threatening, highlighting the need for further studies to better understand their safety profiles and mechanisms of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Public Adverse Event Data Insights into the Safety of Pembrolizumab in Melanoma Patients. Schaefer, A., Sachpekidis, C., Diella, F., 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]

In a phase 2 trial involving 36 patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC), pembrolizumab demonstrated activity, achieving a brain metastasis response in 22% of melanoma patients and 33% of NSCLC patients, with responses being durable for most.

The treatment had an acceptable safety profile, with serious adverse events occurring in a small percentage of patients, indicating that systemic immunotherapy could be a viable option for those with untreated or progressive brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Goldberg, SB., Gettinger, SN., Mahajan, A., et al.[2022]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

In a study of 655 patients with advanced melanoma, pembrolizumab showed an overall objective response rate of 33%, indicating its efficacy in treating this type of cancer.

The median overall survival for patients receiving pembrolizumab was 23 months, with a 12-month survival rate of 66%, while 14% of patients experienced severe treatment-related adverse events, highlighting its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. Ribas, A., Hamid, O., Daud, A., et al.[2022]

In a post hoc analysis of the KEYNOTE-006 study involving 555 patients with advanced melanoma, both ipilimumab and BRAF ± MEK inhibitors showed antitumor activity as subsequent therapies after pembrolizumab, with overall response rates (ORR) of 17.5% for ipilimumab and 30.5% for BRAF ± MEK inhibitors.

Patients who had not previously received BRAF ± MEK inhibitors showed a significantly higher ORR of 43.2% when treated with these agents after pembrolizumab, indicating that prior treatment status may influence the effectiveness of subsequent therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006. Long, GV., Arance, A., Mortier, L., et al.[2022]

References

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

Pembrolizumab superior to ipilimumab in melanoma. [2017]

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

Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab. [2022]

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

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

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

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

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

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. [2022]

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

Pembrolizumab in the management of metastatic melanoma. [2020]

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

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

8. Switzerland pubmed.ncbi.nlm.nih.gov

Public Adverse Event Data Insights into the Safety of Pembrolizumab in Melanoma Patients. [2020]

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

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

10. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. [2022]

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

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

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

Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006. [2022]