Canakinumab + Darbepoetin Alfa for Myelodysplastic Syndrome

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must be taking: Erythropoietin stimulating agents

Must not be taking: Chemotherapeutics, Hypomethylating agents

Disqualifiers: HIV, Hepatitis B/C, Uncontrolled infection, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

13 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is a multi-institution, open-label, Phase 1b/2 clinical trial evaluating the toxicity and efficacy of canakinumab in combination with darbepoetin alfa in patients with lower-risk MDS who have failed prior treatment with an Erythropoietin Stimulating Agent (ESA)

Will I have to stop taking my current medications?

The trial requires that you stop using certain medications, such as chemotherapeutic agents or experimental agents for MDS treatment, at least 14 days before starting the study drugs. Additionally, growth factors must be stopped two weeks prior to the study, and systemic corticosteroids should not be used within 14 days of starting the study drugs.

Is the combination of Canakinumab and Darbepoetin Alfa safe for humans?

Canakinumab has been studied for safety in conditions like systemic juvenile idiopathic arthritis, showing an excellent safety profile with some adverse events reported, including serious ones. The risk of adverse events tends to decrease over time, and safety concerns are more frequent in older patients. ^{1 2 3 4 5}

How is the drug Canakinumab + Darbepoetin Alfa unique for treating myelodysplastic syndrome?

Canakinumab + Darbepoetin Alfa is unique because it combines an anti-inflammatory drug (Canakinumab) with a medication that stimulates red blood cell production (Darbepoetin Alfa), potentially addressing both inflammation and anemia in myelodysplastic syndrome, unlike standard treatments that may focus on only one aspect. ^{6 7 8 9 10}

Research Team

David Sallman, MD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

This trial is for patients with lower-risk Myelodysplastic Syndrome (MDS) who didn't respond to previous Erythropoietin Stimulating Agent treatment. Participants must have adequate organ function, be transfusion dependent or have low hemoglobin levels, and not be pregnant or breastfeeding. They should agree to use contraception and cannot have had certain heart conditions, other cancers within 2 years, or treatments like hypomethylating agents.

Inclusion Criteria

I have been diagnosed with MDS according to WHO standards.

I can take care of myself and perform daily activities.

My organ functions are within normal ranges.

Exclusion Criteria

I have serious heart problems as diagnosed by my doctor.

Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results

I do not have an active, serious infection or uncontrolled fever.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1b: Dose Escalation

Participants receive Canakinumab and Darbepoetin Alfa at escalating doses to determine the maximum tolerated dose

28 days per cohort

1 visit every 28 days

Phase 2: Treatment at Maximum Tolerated Dose

Participants receive Darbepoetin Alfa and the maximum tolerated dose of Canakinumab

Up to 60 months

1 visit every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 60 months

Treatment Details

Interventions

• Canakinumab Injection
• Darbepoetin Alfa

Trial Overview The study tests the combination of Canakinumab Injection with Darbepoetin Alfa in MDS patients who failed prior ESA therapy. It's an open-label Phase 1b/2 trial assessing both the safety (toxicity) and effectiveness (efficacy) of this drug combo.

Participant Groups

Group I: Phase 2: Treatment at Maximum Tolerated Dose Experimental Treatment 2 Interventions

Patients will be treated with Darbepoetin alfa subcutaneously at a dose of 300 mg on days 1 and 15 of each cycle plus the maximum tolerated dose of Canakinumab.

Group II: Phase 1b: Dose Level 2 Experimental Treatment 2 Interventions

Patients will be treated at dose level 2: Canakinumab 300 mg by subcutaneous injection on day 1 of each 28 day cycle. Darbepoetin alfa will be administered subcutaneously at a dose of 300mg on days 1 and 15 of each cycle.

Group III: Phase 1b: Dose Level 1 Experimental Treatment 2 Interventions

Patients will be treated at dose level 1: Canakinumab 150 mg by subcutaneous injection on day 1 of each 28 day cycle. Darbepoetin alfa will be administered subcutaneously at a dose of 300mg on days 1 and 15 of each cycle.

Canakinumab Injection is already approved in United States, European Union for the following indications:

Approved in United States as Ilaris for:

• Cryopyrin-Associated Periodic Syndromes (CAPS)
• Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS)
• Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD)
• Familial Mediterranean Fever (FMF)
• Adult-Onset Still's Disease (AOSD)
• Systemic Juvenile Idiopathic Arthritis (SJIA)
• Gout flares

Approved in European Union as Ilaris for:

• Cryopyrin-Associated Periodic Syndromes (CAPS)
• Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS)
• Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD)
• Familial Mediterranean Fever (FMF)
• Adult-Onset Still's Disease (AOSD)
• Systemic Juvenile Idiopathic Arthritis (SJIA)
• Gout flares

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

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

Findings from Research

In a study assessing the impact of canakinumab on macrophage activation syndrome (MAS) in systemic juvenile idiopathic arthritis (JIA), it was found that the incidence of MAS was similar between canakinumab-treated patients (2.8 cases per 100 patient-years) and those receiving placebo (7.7 cases per 100 patient-years), indicating no significant effect of the drug on MAS risk.

Despite canakinumab effectively controlling systemic JIA in most patients, MAS still occurred, often triggered by infections, and the clinical features of MAS were not altered by the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab. Grom, AA., Ilowite, NT., Pascual, V., et al.[2022]

Canakinumab demonstrated rapid and sustained efficacy in treating systemic juvenile idiopathic arthritis (JIA) in a study of 123 patients, regardless of whether they had fever at the start of treatment, with significant improvements observed by day 15.

The study found that an early response to treatment (adapted ACR Pediatric 50) was a strong predictor of achieving clinical remission, highlighting the importance of early monitoring in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Canakinumab in Patients With Systemic Juvenile Idiopathic Arthritis With and Without Fever at Baseline: Results From an Open-Label, Active-Treatment Extension Study. Brunner, HI., Quartier, P., Alexeeva, E., et al.[2021]

In a study of 475 patients treated with interleukin-1 blockers anakinra (ANA) and canakinumab (CAN), the overall safety profile was found to be excellent, with an adverse event rate of 8.4 per 100 patients per year and serious adverse events occurring in only 14.61% of cases.

Safety concerns were more prevalent in older patients (≥ 65 years) compared to younger patients (< 16 years), but the risk of adverse events decreased over time with continued treatment, indicating that longer treatment durations may lead to improved safety outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of the interleukin-1 inhibitors anakinra and canakinumab in real-life clinical practice: a nationwide multicenter retrospective observational study. Sota, J., Vitale, A., Insalaco, A., et al.[2019]

Canakinumab is effective in treating systemic juvenile idiopathic arthritis (SJIA) in older adolescents and young adults (≥16 years), showing similar efficacy to younger patients, with over 50% achieving significant improvement in symptoms by Day 15.

The safety profile of canakinumab is consistent across different age groups, indicating it is a safe treatment option for both younger and older patients, although one death was reported during the studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of canakinumab in patients with Still's disease: exposure-response analysis of pooled systemic juvenile idiopathic arthritis data by age groups. Feist, E., Quartier, P., Fautrel, B., et al.[2019]

Canakinumab demonstrated long-term efficacy in treating active systemic juvenile idiopathic arthritis (JIA), with 62% of patients achieving a 50% improvement in disease activity after 2 years, and sustained efficacy observed for up to 5 years.

The treatment was associated with a significant reduction in glucocorticoid use, with 15.6% of patients discontinuing and 22% tapering their dosage, while no new safety concerns were identified during the long-term study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Canakinumab in patients with systemic juvenile idiopathic arthritis and active systemic features: results from the 5-year long-term extension of the phase III pivotal trials. Ruperto, N., Brunner, HI., Quartier, P., et al.[2019]

In a study of 420 patients with ankylosing spondylitis who had inadequate responses to biologic treatments, upadacitinib 15 mg once daily showed sustained efficacy over 52 weeks, with 66% of patients achieving significant improvement in disease activity (ASAS40).

The safety profile of upadacitinib remained acceptable, with no new safety risks identified during the study, indicating it is a viable treatment option for patients who have not responded well to other biologic therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of upadacitinib in patients with ankylosing spondylitis refractory to biologic therapy: 1-year results from the open-label extension of a phase III study. Baraliakos, X., van der Heijde, D., Sieper, J., et al.[2023]

In a phase 3 trial involving 314 patients with active non-radiographic axial spondyloarthritis, upadacitinib demonstrated a significant improvement in symptoms compared to placebo, with a 22% higher response rate at week 14 (45% vs 23%).

The safety profile of upadacitinib was comparable to placebo, with similar rates of adverse events and no serious infections or major complications reported, indicating it is a safe treatment option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Upadacitinib for the treatment of active non-radiographic axial spondyloarthritis (SELECT-AXIS 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Deodhar, A., Van den Bosch, F., Poddubnyy, D., et al.[2022]

In a phase 3 trial with 191 participants, azacitidine showed a significant overall response rate of 15.7% in treating myelodysplastic syndrome, compared to no responders in the observation group, indicating its efficacy as a treatment option.

Azacitidine treatment led to a median response duration of at least 9 months, with many patients becoming transfusion independent, and it was generally well-tolerated with no related deaths reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Kaminskas, E., Farrell, A., Abraham, S., et al.[2013]

In a phase 2 trial involving 220 adults with moderate to severe Crohn's disease, upadacitinib demonstrated significant efficacy in inducing endoscopic remission, particularly at the 24 mg dose, compared to placebo.

While upadacitinib showed promising results, it was associated with higher rates of infections and increased cholesterol levels, indicating a need to carefully consider its safety profile in future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease. Sandborn, WJ., Feagan, BG., Loftus, EV., et al.[2021]

In a 24-week phase 3 trial with 1704 patients, upadacitinib (both 15 mg and 30 mg doses) significantly improved ACR20 response rates compared to placebo, indicating its efficacy in treating psoriatic arthritis.

The 30 mg dose of upadacitinib was found to be superior to adalimumab, while both doses were noninferior, suggesting that upadacitinib could be a more effective option for patients who do not respond adequately to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trial of Upadacitinib and Adalimumab for Psoriatic Arthritis. McInnes, IB., Anderson, JK., Magrey, M., et al.[2021]

References

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

Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab. [2022]

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

Efficacy and Safety of Canakinumab in Patients With Systemic Juvenile Idiopathic Arthritis With and Without Fever at Baseline: Results From an Open-Label, Active-Treatment Extension Study. [2021]

3. Germany pubmed.ncbi.nlm.nih.gov

Safety profile of the interleukin-1 inhibitors anakinra and canakinumab in real-life clinical practice: a nationwide multicenter retrospective observational study. [2019]

4. Italy pubmed.ncbi.nlm.nih.gov

Efficacy and safety of canakinumab in patients with Still's disease: exposure-response analysis of pooled systemic juvenile idiopathic arthritis data by age groups. [2019]

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

Canakinumab in patients with systemic juvenile idiopathic arthritis and active systemic features: results from the 5-year long-term extension of the phase III pivotal trials. [2019]

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

Efficacy and safety of upadacitinib in patients with ankylosing spondylitis refractory to biologic therapy: 1-year results from the open-label extension of a phase III study. [2023]

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

Upadacitinib for the treatment of active non-radiographic axial spondyloarthritis (SELECT-AXIS 2): a randomised, double-blind, placebo-controlled, phase 3 trial. [2022]

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

Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. [2013]

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

Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease. [2021]

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

Trial of Upadacitinib and Adalimumab for Psoriatic Arthritis. [2021]