What is the mechanism of action of this treatment?

Neuroblastoma treatments often target specific genetic mutations and pathways involved in tumor growth. ALK inhibitors, such as Lorlatinib, work by blocking the activity of the anaplastic lymphoma kinase (ALK) gene, which can be mutated and drive cancer progression in some Neuroblastoma patients. By inhibiting ALK, these drugs can reduce tumor growth and spread. This targeted approach is crucial for Neuroblastoma patients as it offers a more personalized treatment option, potentially leading to better outcomes and fewer side effects compared to conventional chemotherapy.

What side effects are associated with this type of intervention?

Common treatments for neuroblastoma, particularly ALK inhibitors like Lorlatinib, are associated with side effects such as liver function abnormalities, dizziness, and neutropenia. Crizotinib, another ALK inhibitor, has been linked to severe toxicities affecting liver, cardiac, and lung functions, as well as erosive esophagitis. Broadly, neuroblastoma treatments, including chemotherapy and radiation, can cause myelosuppression, gastrointestinal disturbances, and potential long-term organ damage.

What prior FDA approvals exist?

The FDA has approved several treatments for neuroblastoma, particularly focusing on targeted therapies. One notable example is Crizotinib, an ALK inhibitor, which has been used for ALK-positive neuroblastoma. Lorlatinib, another ALK inhibitor, is currently being studied for its efficacy in treating relapsed/refractory neuroblastoma. These treatments target specific genetic mutations in neuroblastoma cells, offering a more personalized approach to therapy.

What other types of research exist?

Promising novel alternatives to Lorlatinib for Neuroblastoma patients include: 1) Crizotinib, another ALK inhibitor with demonstrated activity in pediatric patients with refractory solid tumors or anaplastic large-cell lymphoma. 2) Dinutuximab, an anti-disialoganglioside antibody, in combination with GM-CSF, which has shown efficacy in recurrent neuroblastoma. 3) Selumetinib, a MEK inhibitor, which has shown promise in pediatric low-grade gliomas and may be applicable to neuroblastoma. 4) Pembrolizumab, an immune checkpoint inhibitor, which has shown activity in various sarcomas and may offer benefits in neuroblastoma.

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ALK Inhibitor

Lorlatinib for Neuroblastoma

Phase 1

Waitlist Available

Research Sponsored by New Approaches to Neuroblastoma Therapy Consortium

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

All patients must have at least one of the following: Recurrent/progressive disease after the diagnosis of high-risk neuroblastoma, refractory disease, or persistent disease

Patients must have a life expectancy of at least 12 weeks and a Lansky (≤16 years) or Karnofsky (>16 years) score of at least 50

Must not have

Patients with an active or uncontrolled infection

Patient with current history of suicidal ideation and history of suicide attempt in their lifetime

Timeline

Screening 3 weeks

Treatment Varies

Follow Up all toxicities from enrollment until completion of course 2 (day 56)

Awards & highlights

All Individual Drugs Already Approved

No Placebo-Only Group

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Possible side effects include reactions related to liver function changes, blood cell counts alterations leading to increased infection risk, potential kidney issues, heart problems like altered heart rhythm or function, as well as general symptoms such as fatigue.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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

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

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I have been diagnosed with neuroblastoma confirmed by tests.

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My neuroblastoma is classified as high-risk.

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My neuroblastoma cancer has spread to my bone marrow.

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My tumor has an ALK mutation confirmed by a certified test.

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I have recovered from side effects of my previous cancer treatments.

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I have a lesion that tested positive for neuroblastoma or ganglioneuroblastoma.

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I have a tumor that can be measured.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I do not have any ongoing or uncontrolled infections.

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

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

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I have had a stem cell transplant from a donor.

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My major organs are healthy enough to handle treatment.

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I have a history of HIV, hepatitis B, or hepatitis C.

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I am currently receiving hemodialysis.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ all toxicities from enrollment until completion of course 2 (day 56)

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~all toxicities from enrollment until completion of course 2 (day 56)

This trial's timeline: 3 weeks for screening, Varies for treatment, and all toxicities from enrollment until completion of course 2 (day 56) for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Describe Hematological Toxicities (A1 and B1)

Describe Hematological Toxicities (A2)

Describe Hematological Toxicities (B2)

+6 more

Secondary study objectives

Overall Response A1 and B1

Overall Response A2

Overall Response B2

+3 more

Side effects data

From 2020 Phase 1 trial • 29 Patients • NCT03542305

13%

Diarrhoea

13%

Ecchymosis

13%

Dizziness

13%

Headache

13%

Upper respiratory tract infection

13%

Skin abrasion

100%

80%

60%

40%

20%

Study treatment Arm

Moderate Impairment

Severe Impairment

Mild Impairment

Normal Function

Awards & Highlights

All Individual Drugs Already Approved

Therapies where all constituent drugs have already been approved are likely to have better-understood side effect profiles.

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

4Treatment groups

Experimental Treatment

Group I: Cohort B2 (Combined w/ chemotherapy)Experimental Treatment4 Interventions

Lorlatinib will be given orally once daily continuously for 28 days, at the RP2D defined by cohort A1. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle.

Group II: Cohort B1 (Expansion)Experimental Treatment1 Intervention

Lorlatinib will be given orally once daily continuously for 28 days at the RP2D defined by cohort A1. This cohort will not begin enrollment until the recommended phase 2 dose is established from the dose escalation cohort A1.

Group III: Cohort A2 (Adult and large BSA)Experimental Treatment1 Intervention

Lorlatinib will be given at the adult recommended phase 2 dose (RP2D) of 100 mg orally once daily continuously for 28 days.

Group IV: Cohort A1 (Dose-finding)Experimental Treatment1 Intervention

Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be assigned at the time of study registration. The starting dose for cohort A1 is 45 mg/m2/dose

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Topotecan

2017

Completed Phase 3

~2460

Lorlatinib

2018

Completed Phase 4

~530

Cyclophosphamide

2010

Completed Phase 4

~2310

0 / 16Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Neuroblastoma treatments often target specific genetic mutations and pathways involved in tumor growth. ALK inhibitors, such as Lorlatinib, work by blocking the activity of the anaplastic lymphoma kinase (ALK) gene, which can be mutated and drive cancer progression in some Neuroblastoma patients. By inhibiting ALK, these drugs can reduce tumor growth and spread. This targeted approach is crucial for Neuroblastoma patients as it offers a more personalized treatment option, potentially leading to better outcomes and fewer side effects compared to conventional chemotherapy.

Paediatric Strategy Forum for medicinal product development of multi-targeted kinase inhibitors in bone sarcomas: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.Pediatric drug development: a perspective from the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI).Therapeutic approaches for relapsed/refractory adult acute lymphoblastic leukemia (ALL), a review on monoclonal antibodies and targeted therapies.