Lorlatinib for Neuroblastoma

No longer recruiting at 14 trial locations

Overseen By Araz Marachelian, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: New Approaches to Neuroblastoma Therapy Consortium

Must not be taking: CYP34A inhibitors, inducers, substrates

Disqualifiers: Pregnancy, HIV, Hepatitis B/C, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called lorlatinib (also known as Lorbrena) to determine its effectiveness in treating neuroblastoma, a cancer affecting nerve cells, particularly in children. The trial aims to find the right dose for children and assess its efficacy alone or with chemotherapy. It targets patients with high-risk neuroblastoma that has recurred or not responded well to other treatments. Individuals with an ALK gene change in their tumor who have struggled with standard treatments might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that you cannot take other anti-cancer agents, certain steroids, or drugs that affect CYP34A enzymes. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that lorlatinib has been tested in both children and adults for treating neuroblastoma, a type of cancer. Studies have found that lorlatinib, whether used alone or with chemotherapy, is generally safe and tolerable. Most people have managed the treatment well, with controllable side effects.

In these studies, common side effects included mood changes, higher cholesterol levels, and weight gain. However, these were not severe for most participants. This trial is in the early stages, so researchers are still determining the safest and most effective dose.

While lorlatinib is still being tested for neuroblastoma, its use in other conditions suggests a known safety profile. Those considering joining a trial should discuss the possible risks and benefits with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for neuroblastoma?

Researchers are excited about Lorlatinib for neuroblastoma because it offers a unique mechanism of action, targeting specific genetic mutations known as ALK and ROS1, which are not directly targeted by current treatments. Unlike standard chemotherapy, Lorlatinib is a targeted therapy that may offer more precision and potentially fewer side effects by honing in on these specific molecular targets. Additionally, Lorlatinib is administered orally, which could provide more convenience compared to some traditional treatments that require intravenous administration. This targeted approach could lead to improved outcomes for patients who have these specific genetic mutations.

What evidence suggests that lorlatinib might be an effective treatment for neuroblastoma?

Previous studies have shown that lorlatinib holds promise for treating neuroblastoma, particularly in patients with ALK mutations. Research indicates that lorlatinib effectively reaches the brain, leading to positive outcomes. In one study, 33% of patients responded to the treatment, with some experiencing long-lasting benefits. This trial tests lorlatinib in various treatment arms, with some participants receiving it alone and others in combination with chemotherapy. Lorlatinib has proven safe and effective for people of different ages, suggesting it might be a strong option for those with relapsed or difficult-to-treat neuroblastoma. ^{1 2 3 6 7}

Who Is on the Research Team?

Yael Mosse, MD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for children and adults with high-risk neuroblastoma that's come back or hasn't responded to treatment. They must have certain types of tumor cells in their bone marrow, a life expectancy over 12 weeks, and good organ function. They can't have had lorlatinib before but other ALK inhibitors are okay. No recent cancer treatments or uncontrolled illnesses.

Inclusion Criteria

My neuroblastoma has come back, is not responding, or hasn't gone away.

Patients must have specific imaging criteria for MIBG avid or non-avid tumors

I am expected to live at least 12 weeks and can do some daily activities on my own.

Exclusion Criteria

I do not have any ongoing or uncontrolled infections.

I have thought about suicide recently and have attempted it before.

I have chosen not to participate in the NANT 2004-05 study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (Cohort A1)

Lorlatinib is administered orally once daily for 28 days to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) using a 3+3 design.

4 weeks

Continuous daily dosing

Expansion (Cohort B1)

Once RP2D is established, an expansion cohort of 6 patients will receive lorlatinib at the RP2D for 28 days.

4 weeks

Continuous daily dosing

Combination with Chemotherapy (Cohort B2)

Lorlatinib is administered in combination with chemotherapy (Cyclophosphamide and Topotecan) for 28 days, with lorlatinib given at least one hour prior to chemotherapy on days 1-5 of each cycle.

4 weeks

Continuous daily dosing with chemotherapy on days 1-5

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of toxicities and overall response.

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Lorlatinib

Trial Overview The study tests Lorlatinib alone and with chemotherapy (Topotecan, Cyclophosphamide) in patients whose neuroblastoma has relapsed or is resistant to treatment. It starts by finding the safest dose of Lorlatinib (Phase 1), then expands to more patients once the right dose is found.

How Is the Trial Designed?

Group I: Cohort B2 DL5B Experimental Treatment 4 Interventions

Lorlatinib will be given orally once daily continuously for 28 days at 115mg/m2/dose. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle. Patients must be under 18 years of age at time of enrollment.

Group II: Cohort B2 DL4B Experimental Treatment 4 Interventions

Lorlatinib will be given orally once daily continuously for 28 days at 95mg/m2/dose. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle. Patients must be under 18 years of age at time of enrollment.

Group III: Cohort B2 DL4A Experimental Treatment 4 Interventions

Lorlatinib will be given orally once daily continuously for 28 days at 150mg/day. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle. Patients must be 18 years of age or older at time of enrollment.

Group IV: Cohort B2 DL3A Experimental Treatment 4 Interventions

Lorlatinib will be given orally once daily continuously for 28 days at 100mg/day. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle. Patients must be 18 years of age or older at time of enrollment.

Group V: Cohort B1 DL5 Experimental Treatment 1 Intervention

Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 115 mg/m2/dose. Patients must be under 18 years of age at time of enrollment.

Group VI: Cohort A2 DL4A Expansion Experimental Treatment 1 Intervention

Lorlatinib will be given at 150 mg orally once daily continuously for 28 days. Patients must be 18 years of age or older at time of enrollment.

Group VII: Cohort A2 DL4A Experimental Treatment 1 Intervention

Lorlatinib will be given at 150 mg orally once daily continuously for 28 days. Patients must be 18 years of age or older at time of enrollment.

Group VIII: Cohort A2 DL 3A Experimental Treatment 1 Intervention

Lorlatinib will be given at 100 mg orally once daily continuously for 28 days. Patients must be 18 years of age or older at time of enrollment.

Group IX: Cohort A1 DL5 Experimental Treatment 1 Intervention

Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 115 mg/m2/dose. Patients must be under 18 years of age at time of enrollment.

Group X: Cohort A1 DL4 Experimental Treatment 1 Intervention

Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 95 mg/m2/dose. Patients must be under 18 years of age at time of enrollment.

Group XI: Cohort A1 DL3 Experimental Treatment 1 Intervention

Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 75 mg/m2/dose. Patients must be under 18 years of age at time of enrollment.

Group XII: Cohort A1 DL2 Experimental Treatment 1 Intervention

Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 60 mg/m2/dose. Patients must be under 18 years of age at time of enrollment.

Group XIII: Cohort A1 DL1 Experimental Treatment 1 Intervention

Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 45 mg/m2/dose. Patients must be under 18 years of age at time of enrollment.

Lorlatinib is already approved in United States, European Union, Japan, Canada for the following indications:

Approved in United States as Lorbrena for:

• Metastatic non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement

Approved in European Union as Lorbrena for:

• Advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement

Approved in Japan as Lorbrena for:

• Unresectable, advanced/recurrent non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement

Approved in Canada as Lorbrena for:

• Metastatic non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement

Who Is Running the Clinical Trial?

New Approaches to Neuroblastoma Therapy Consortium

Lead Sponsor

Trials

19

Recruited

1,700+

Ronan Thompson Foundation

Collaborator

Trials

1

Recruited

70+

University of Southern California

Collaborator

Trials

956

Recruited

1,609,000+

The Band of Parents

Collaborator

Trials

2

Recruited

110+

Wade's Army

Collaborator

Trials

2

Recruited

70+

The Catherine Elizabeth Blair Memorial Foundation

Collaborator

Trials

1

Recruited

70+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Children's Neuroblastoma Cancer Foundation

Collaborator

Trials

1

Recruited

70+

Solving Kids' Cancer US/EU

Collaborator

Trials

2

Recruited

110+

Cookies for Kids' Cancer

Collaborator

Trials

7

Recruited

360+

Published Research Related to This Trial

Rovalpituzumab tesirine (Rova-T) demonstrated anti-tumor activity in preclinical models of neuroblastoma, showing a clear dose-response effect with complete or partial responses in 3 out of 11 models tested, and stable disease in another 3 models, without significant toxicity observed.

DLL3 was found to be overexpressed in neuroblastoma, but its variable expression in human tumors indicates that clinical trials using Rova-T should include a companion diagnostic to ensure proper patient selection based on DLL3 expression levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the DLL3-targeting antibody-drug conjugate rovalpituzumab tesirine in preclinical models of neuroblastoma. Krytska, K., Casey, CE., Pogoriler, J., et al.[2023]

A phase 1 study demonstrated that lorlatinib is both safe and effective for children with treatment-refractory or relapsed ALK-driven neuroblastoma, highlighting its potential as a new treatment option.

These preliminary findings suggest that lorlatinib could provide hope for young patients who have not responded to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of lorlatinib against ALK-driven refractory or relapsed neuroblastoma. Suk, Y., Singh, SK.[2023]

In a phase-II trial involving patients with relapsed high-risk neuroblastoma, a chemotherapy regimen including topotecan, cyclophosphamide, and etoposide showed a 61% response rate in relapsed patients and a 72% response rate in untreated patients, indicating its efficacy.

The treatment was generally well-tolerated, with significant myelotoxicity (like leukopenia and thrombocytopenia) being the main side effects, but no fatal toxicities were reported, suggesting that the benefits may outweigh the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial. Simon, T., Längler, A., Harnischmacher, U., et al.[2018]

Citations

1. nature.com nature.com/articles/s41591-023-02297-5

Lorlatinib with or without chemotherapy in ALK-driven ... Lorlatinib was optimized to penetrate the blood–brain barrier, leading to improved CNS distribution as well as intracranial responses in ...

2. chop.edu chop.edu/news/researchers-show-lorlatinib-safe-effective-patients-high-risk-neuroblastoma

Researchers Show Lorlatinib is Safe, Effective for Patients ... Researchers found that lorlatinib given alone or in combination with chemotherapy was safe and tolerable in pediatric, adolescent, and adult patients with ...

3. winshipcancer.emory.edu winshipcancer.emory.edu/newsroom/articles/2023/researchers-show-lorlatinib-is-safe-and-effective-for-patients-with-alk-driven-relapsedrefractory-high-risk-neuroblastoma.php

Researchers show lorlatinib is safe and effective for ... Phase 1 study shows lorlatinib holds significant promise in the treatment of newly diagnosed ALK-driven high-risk neuroblastoma.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11292203/

Sequential Analysis of cfDNA Reveals Clonal Evolution in ... Overall response rate to lorlatinib was 33% (CI, 13%–59%), with response observed in 6/10 cases without versus 0/8 cases with MYCN amplification ...

5. aacrjournals.org aacrjournals.org/cancerrescommun/article/4/9/2553/748729/Long-Lasting-Response-to-Lorlatinib-in-Patients

Long-Lasting Response to Lorlatinib in Patients with ALK ... We conclude that some patients with relapsed or refractory high-risk neuroblastoma show durable responses to lorlatinib as monotherapy, and targeted ctDNA ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37012551/

Lorlatinib with or without chemotherapy in ALK ... - PubMed We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2666379123001908

Safety and efficacy of lorlatinib against ALK-driven ... A phase 1 first-in-child study showcasing the safety and efficacy of lorlatinib against treatment-refractory or relapsed ALK-driven neuroblastoma.