Lorlatinib for Neuroblastoma

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

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

65 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests Lorlatinib, a new drug that blocks proteins helping cancer grow, in children whose neuroblastoma has returned or not responded to other treatments. The goal is to find the best dose and see how well it works.

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.

What data supports the effectiveness of the drug Lorlatinib for treating neuroblastoma?

Research shows that Lorlatinib, a drug used for ALK-driven neuroblastoma, has shown promise in early trials. In children, the drug alone had a 30% response rate, and when combined with chemotherapy, the response rate increased to 63%, indicating its potential effectiveness. ^{1 2 3 4 5}

Is lorlatinib safe for use in humans?

Lorlatinib has been tested in children and adults with neuroblastoma, showing common side effects like high triglycerides (a type of fat in the blood), high cholesterol, and weight gain. Some adults experienced changes in behavior, which improved when the dose was adjusted. ^{1 2 6 7 8}

What makes the drug Lorlatinib unique for treating neuroblastoma?

Lorlatinib is unique for treating neuroblastoma because it is a third-generation ALK inhibitor specifically effective against ALK-driven neuroblastoma that is resistant to other treatments like crizotinib. It can be used alone or in combination with chemotherapy, showing promising results in both children and adults with relapsed or refractory neuroblastoma. ^{1 2 9 10 11}

Research Team

Yael Mosse, MD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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 Experimental Treatment 1 Intervention

Lorlatinib will be given orally once daily continuously for 28 days at the RP2D defined by cohort A1 (115mg/m2/dose). This cohort will not begin enrollment until the recommended phase 2 dose is established from the dose escalation cohort A1. Patients must be under 18 years of age at time of enrollment.

Group VI: Cohort A2 Expansion 4A 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 4A 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 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+

Findings from Research

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]

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]

References

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

Safety and efficacy of lorlatinib against ALK-driven refractory or relapsed neuroblastoma. [2023]

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

Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results. [2023]

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

Rapid-sequence tandem transplant for children with high-risk neuroblastoma. [2019]

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

Acetazolamide potentiates the anti-tumor potential of HDACi, MS-275, in neuroblastoma. [2018]

5. Germany pubmed.ncbi.nlm.nih.gov

Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial. [2018]

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

Evaluation of the DLL3-targeting antibody-drug conjugate rovalpituzumab tesirine in preclinical models of neuroblastoma. [2023]

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

Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. [2021]

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

A phase II study of irinotecan in children with relapsed or refractory neuroblastoma: a European cooperation of the Société Française d'Oncologie Pédiatrique (SFOP) and the United Kingdom Children Cancer Study Group (UKCCSG). [2018]

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

Novel multiple tyrosine kinase inhibitor ponatinib inhibits bFGF-activated signaling in neuroblastoma cells and suppresses neuroblastoma growth in vivo. [2019]

10. Ireland pubmed.ncbi.nlm.nih.gov

Small molecule inhibitor agerafenib effectively suppresses neuroblastoma tumor growth in mouse models via inhibiting ERK MAPK signaling. [2020]

11. Greece pubmed.ncbi.nlm.nih.gov

EGFR inhibition using gefitinib is not active in neuroblastoma cell lines. [2018]