Crovalimab for Sickle Cell Disease

(CROSSWALK-a Trial)

No longer recruiting at 34 trial locations

Overseen By Reference Study ID Number: BO42452 https://forpatients.roche.com/

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Hoffmann-La Roche

Disqualifiers: Frequent VOEs, Severe infection, HIV, others

Compensation: Varies

Number of Visits: 1

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of a new drug, crovalimab, for individuals with sickle cell disease (SCD) who require hospital care due to a severe pain crisis. The main goal is to assess the safety of crovalimab and understand how the body processes and reacts to it. Participants will receive either crovalimab or a placebo (a substance with no active drug). Eligible participants have sickle cell anemia or a similar condition, are currently experiencing a pain crisis requiring hospital admission, and meet specific health criteria, such as stable liver and kidney function. As a Phase 1 trial, this research focuses on understanding how crovalimab works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications to join the trial?

The protocol does not specify if you need to stop your current medications. However, if you are on SCD-directed therapies, you must be on a stable dose for at least 28 days before joining the trial.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on sickle cell disease-directed therapies, you must be on a stable dose for at least 28 days before joining the trial.

Is there any evidence suggesting that crovalimab is likely to be safe for humans?

Research shows that crovalimab is under study to determine its safety in treating pain crises in sickle cell disease. Previous studies have examined its tolerability and safety. These studies primarily focus on safety, with researchers closely monitoring any side effects.

Currently, detailed information about side effects is limited. As this trial is in an early phase, the treatment's safety remains under close scrutiny. Early-phase trials often emphasize safety and help understand the body's reaction to the treatment. Researchers are also comparing crovalimab to a placebo (a substance with no active drug) to determine if any effects result from the treatment itself.

In summary, crovalimab is in the early stages of testing for sickle cell disease, with its safety under close observation. Those considering joining this trial should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for sickle cell disease?

Unlike the standard treatments for sickle cell disease, which often involve managing symptoms and preventing complications through blood transfusions and hydroxyurea, Crovalimab offers a novel approach by targeting the complement system. Crovalimab is a monoclonal antibody designed to inhibit the C5 protein, potentially reducing the frequency and severity of pain crises. This targeted mechanism may provide a more direct and effective way to manage sickle cell disease, which is why researchers are excited about its potential.

What evidence suggests that crovalimab might be an effective treatment for sickle cell disease?

Research has shown that crovalimab might help manage pain crises in people with sickle cell disease (SCD). This trial will administer either crovalimab or a placebo to participants to evaluate its effectiveness. In studies with SCD patients, researchers have tested crovalimab to see if it can prevent painful episodes caused by blocked blood flow, known as vaso-occlusive events (VOEs). Early results suggested that crovalimab, compared to a placebo, might reduce the frequency of these painful events. While more detailed results are still being collected, the treatment has shown promise in easing symptoms related to SCD. Overall, researchers are carefully studying crovalimab to confirm its potential benefits for people with sickle cell disease. ^{2 3 4 6 7}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

This trial is for adults and teens with Sickle Cell Disease who weigh at least 40 kg, have had certain vaccinations, stable sickle cell therapies if any, good liver/kidney function, and not pregnant. They must be hospitalized for a pain crisis but can't join if they've had recent surgeries, severe infections, many pain crises in the past year or are on other experimental treatments.

Inclusion Criteria

My liver and kidneys are working well.

I have been on a stable dose of my sickle cell treatment for at least 28 days.

I am hospitalized for a painful sickle cell crisis needing strong pain medication.

Exclusion Criteria

I've had over 10 pain crises needing hospital visits in the last year.

My pain from the current episode has lasted more than 48 hours.

I have had a stem cell transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single intravenous (IV) infusion of Crovalimab or placebo based on body weight

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety, pharmacokinetics, pharmacodynamics, and efficacy after treatment

12 weeks

Multiple visits (in-person and/or virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Crovalimab
• Placebo

Trial Overview The study tests Crovalimab against a placebo to manage acute uncomplicated Vaso-Occlusive Episodes (VOE) requiring hospital care in Sickle Cell Disease patients. It focuses on safety while also checking how the body processes and responds to Crovalimab and its initial effectiveness.

How Is the Trial Designed?

Group I: Crovalimab Experimental Treatment 1 Intervention

Participants will receive a single intravenous (IV) infusion of Crovalimab based on body weight.

Group II: Placebo Placebo Group 1 Intervention

Participants will receive a single IV infusion of matching Placebo.

Who Is Running the Clinical Trial?

Hoffmann-La Roche

Lead Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Published Research Related to This Trial

Ofatumumab is an effective treatment option for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who have not responded to previous therapies like fludarabine and alemtuzumab, demonstrating activity against rituximab-resistant CLL cell lines.

The review highlights that front-line chemoimmunotherapy has improved overall survival rates in CLL compared to traditional chemotherapy, showcasing advancements in treatment strategies over the past decade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging role of ofatumumab in the treatment of chronic lymphocytic leukemia. Nabhan, C., Kay, NE.[2021]

Crizanlizumab, a monoclonal antibody targeting P-selectin, received conditional marketing authorization in the EU for preventing recurrent vaso-occlusive crises in sickle cell disease patients aged 16 and older, showing a 45.3% reduction in annual pain crises at a high dose compared to placebo.

The treatment was found to have a similar safety profile to placebo, with common side effects including infusion-related reactions and arthralgia, indicating that crizanlizumab is both effective and relatively safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Medicines Agency Review of Crizanlizumab for the Prevention of Recurrent Vaso-Occlusive Crises in Patients With Sickle Cell Disease. Delgado, J., Voltz, C., Stain, M., et al.[2021]

In a phase 2 study of 342 untreated patients with non-del(11q) chronic lymphocytic leukemia (CLL), the combination of fludarabine plus lenalidomide (FR+L) and fludarabine plus cyclophosphamide (FCR) showed significantly better 2-year progression-free survival (PFS) rates (72% and 74%, respectively) compared to the historical control rate of 60%.

The study found that FR+L and FCR not only improved PFS but also demonstrated longer median overall survival (OS), with FCR achieving a median OS of 101 months, suggesting that incorporating lenalidomide into treatment regimens could enhance outcomes for CLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide consolidation benefits patients with CLL receiving chemoimmunotherapy: results for CALGB 10404 (Alliance). Byrd, JC., Ruppert, AS., Heerema, NA., et al.[2020]

Monoclonal antibodies like rituximab, alemtuzumab, and gemtuzumab ozogamicin are effective treatments for various blood cancers, including malignant lymphoma and different types of leukemia, showcasing their role in modern cancer therapy.

New targeted therapies such as dasatinib and nilotinib are being used for chronic myelogenous leukemia patients who become resistant to imatinib, while drugs like thalidomide and bortezomib are proving effective in treating multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Novel medical treatment modalities in hematology]. Hasselbalch, HC., Birgens, H., Dufva, IH., et al.[2022]

Anti-CD20 antibodies, such as rituximab, ofatumumab, and obinutuzumab, have significantly improved response rates and survival in patients with chronic lymphocytic leukemia when added to chemotherapy regimens.

Newer anti-CD20 antibodies like ocaratuzumab, veltuzumab, and ublituximab are currently being tested in clinical trials, potentially expanding treatment options and allowing for combinations with novel small molecule agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dancing partners at the ball: Rational selection of next generation anti-CD20 antibodies for combination therapy of chronic lymphocytic leukemia in the novel agents era. Butler, LA., Tam, CS., Seymour, JF.[2018]

In a real-world study comparing new sickle cell disease treatments (L-glutamine, voxelotor, crizanlizumab) to hydroxyurea, the rates of adverse events (AEs) were found to be lower than those reported in clinical trials, indicating a potentially safer profile for these new agents.

The study revealed that the types of AEs varied by treatment, emphasizing the importance of effective communication between patients and physicians to better understand and manage patient-reported symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative pharmacovigilance assessment of adverse events associated with the use of hydroxyurea, L-glutamine, voxelotor, and crizanlizumab in sickle cell disease. Chen, M., Hankins, JS., Zhang, M., et al.[2023]

In a study of 118 patients with Crohn's disease treated with adalimumab, 81.3% achieved a clinical response (complete or partial) within one year, demonstrating its effectiveness in real-world clinical practice.

Adalimumab was generally well tolerated, but 54% of patients experienced adverse events, with 11% facing serious adverse events, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adalimumab for Crohn's disease in clinical practice at Mayo clinic: the first 118 patients. Swoger, JM., Loftus, EV., Tremaine, WJ., et al.[2018]

In a study of 117 Crohn's disease patients who previously failed anti-TNF therapy, those on a high-dose adalimumab regimen (40 mg weekly or 80 mg every other week) experienced a significantly longer time to treatment failure (6.6 years) compared to those on a standard-dose regimen (40 mg every other week), which had a median time to failure of 3.0 years.

The high-dose regimen also demonstrated a lower hazard rate of treatment failure (hazard ratio: 0.27), indicating it is more effective, while safety profiles were similar between high-dose and standard-dose groups, with no significant difference in adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of higher adalimumab maintenance therapy versus standard dose in anti-tumor necrosis factor experienced Crohn's disease patients: A propensity-score matched cohort analysis. Narula, N., Wong, ECL., AlRamdan, R., et al.[2022]

In 2016, significant advancements in hematologic cancer treatment were made with the approval of venetoclax, a first-in-class B-cell lymphoma 2 inhibitor, and nivolumab, the first immune checkpoint inhibitor for hematologic malignancies, enhancing patient management options.

The approval of defibrotide for veno-occlusive disease and expanded uses for anti-CD20 and anti-CD38 monoclonal antibodies indicate a growing arsenal of targeted therapies, each with specific mechanisms of action and clinical contexts for use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel and Expanded Oncology Drug Approvals of 2016-PART 2: New Options in the Management of Hematologic Malignancies. Knepper, TC., Saller, J., Walko, CM.[2018]

Crizanlizumab is the first monoclonal antibody approved for sickle cell disease, specifically designed to reduce the frequency of vaso-occlusive pain crises, based on data from a phase 2 clinical trial.

This medication is administered as a monthly intravenous infusion for patients aged 16 and older, showing efficacy in crisis prevention, although concerns about cost and long-term safety remain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizanlizumab for the Prevention of Vaso-Occlusive Pain Crises in Sickle Cell Disease. Stevens, DL., Hix, M., Gildon, BL.[2022]

Crizanlizumab may help reduce acute care visits for patients with sickle cell disease, especially among those who frequently use hospital services, with a significant decrease from an average of 40 visits to 16 after starting treatment.

Despite its potential benefits, the study found a high discontinuation rate, with only five out of fifteen patients remaining on crizanlizumab six months after starting, indicating a need for further research into the reasons for discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Data of Crizanlizumab in Sickle Cell Disease: A Single-Center Analysis. Cheplowitz, H., Block, S., Groesbeck, J., et al.[2023]

Current therapies for sickle cell anemia, such as hydroxyurea, work by increasing fetal hemoglobin (Hb F) levels, which helps reduce the harmful effects of sickle hemoglobin (Hb S) polymerization.

Emerging treatments are being explored that target various mechanisms, including increasing cell volume to lower Hb S concentration, inhibiting adhesion molecules to prevent vaso-occlusion, and promoting vasodilation through nitric oxide and antioxidants, potentially leading to improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Promising therapies in sickle cell disease. Raghupathy, R., Billett, HH.[2019]

Crizanlizumab is a monoclonal antibody that effectively reduces the frequency of vaso-occlusive crises (VOCs) in patients with sickle cell disease by blocking P-selectin, which is crucial for cell adhesion and inflammation.

Approved in the USA in November 2019 for adults and pediatric patients aged 16 and older, crizanlizumab is also under review in the EU and being studied for use in myelofibrosis, indicating its potential versatility in treating blood-related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizanlizumab: First Approval. Blair, HA.[2020]

In a study of 27 children with Crohn disease who had previously failed infliximab treatment, adalimumab (ADA) was found to be effective in 70% of the patients after a median follow-up of 16 months.

ADA treatment was associated with a significant decrease in inflammatory markers (C-reactive protein and orosomucoid) without serious adverse effects, indicating it is a safe option for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of adalimumab after infliximab failure in pediatric Crohn disease. Fumery, M., Jacob, A., Sarter, H., et al.[2022]

The review highlights that while treatments for Crohn's disease and ulcerative colitis, such as azathioprine, mercaptopurine, methotrexate, and biologic therapies, can be effective, they are associated with a range of adverse events, including serious complications like infections and malignancies.

It emphasizes the importance of gastroenterologists communicating the risks and benefits of these therapies to patients, and provides strategies for discussing when it may be appropriate to modify or discontinue treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events in IBD: to stop or continue immune suppressant and biologic treatment. McLean, LP., Cross, RK.[2023]

Citations

1. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/1158/504385/Trials-in-Progress-The-Randomized-Double-Blind

Trials in Progress: The Randomized, Double-Blind, Placebo ... Here, we describe two randomized, double-blind, placebo-controlled trials evaluating crovalimab in pts with SCD: CROSSWALK-a (Phase 1b; NCT04912869) and ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05075824

NCT05075824 | A Study Evaluating the Efficacy, Safety, ... This study is designed to evaluate the efficacy, safety and pharmacokinetics of crovalimab compared with placebo as adjunct therapy in the prevention of VOEs in ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10112618/

5610823 TRIAL IN PROGRESS A randomized, double-blind, placebo-controlled, Phase 1b study evaluating the safety of crovalimab in managing acute uncomplicated VOEs in pts with SCD.

4. genentech-clinicaltrials.com genentech-clinicaltrials.com/en/trials/blood-disorder/sickle-cell-disease/a-study-evaluating-the-efficacy--safety--pharmacokineti-50959.html

Clinical Trial – Sickle Cell Disease – Efficacy, Safety, ... The purpose of this clinical trial is to compare the effects, good or bad, of crovalimab versus placebo on patients with SCD. In this clinical trial, you will ...

5. academic.oup.com academic.oup.com/jscd/article/1/Supplement_1/yoae002.009/7686668

Randomized Phase 1b CROSSWALK-a and Phase 2a ... We describe the design of two randomized, double-blind, placebo-controlled trials evaluating crovalimab in patients with SCD.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05075824

NCT05075824 | A Study Evaluating the Efficacy, Safety, ... This study is designed to evaluate the efficacy, safety and pharmacokinetics of crovalimab compared with placebo as adjunct therapy in the prevention of VOEs ...

7. genentech-clinicaltrials.com genentech-clinicaltrials.com/en/trials/blood-disorder/sickle-cell-disease/a-study-evaluating-the-safety--pharmacokinetics--pharma-03990.html

Clinical Trial – Sickle Cell Disease – Safety, Pharmacoki... You will have a 2 in 3 (67%) chance of being in the crovalimab group and a 1 in 3 (33%) chance of being in the placebo group. During the clinical trial, you can ...