9 december 2020: Bron: FDA

De FDA - Food and Drug Administration geeft op basis van twee relatief kleine studies een versnelde goedkeuring aan de combinatie behandeling van het anti-lichaam medicijn naxitamab plus Granulocyte- Macrophage Colony Stimulating Factor (GM-CSF) voor hoog-risico neuroblastoom in het bot of het beenmerg.

De werkzaamheid werd geconstateerd in twee verschillende studies bij patiënten met recidiverend of refractair neuroblastoom in het bot of beenmerg.

Het gaat om deze twee studies, klik op de titels voor omschrijving studieprotocol. Onderaan dit artikel abstracten van de studies:

Studie 1: Combination Therapy of Antibody Hu3F8 With Granulocyte- Macrophage Colony Stimulating Factor (GM-CSF) in Patients With Relapsed/Refractory High-Risk Neuroblastoma

Studie 2: Naxitamab for High-Risk Neuroblastoma Patients With Primary Refractory Disease or Incomplete Response to Salvage Treatment in Bone and/or Bone Marrow

Patiënten kregen 3 mg / kg naxitamab toegediend als intraveneuze infusie op dag 1, 3 en 5 van elke cyclus van 4 weken in combinatie met GM-CSF subcutaan met 250 µg / m2 / dag op dag -4 tot 0 en in 500 µg / m2 / dag op dag 1 tot 5. Naar goeddunken van de onderzoeker mochten patiënten vooraf geplande bestraling krijgen op de primaire ziekteplaats in studie 1 en bestralingstherapie voor tumoren buiten de botten of beenmerg of ziekte van zacht weefsel in studie 2.

Van de 22 patiënten die in studie 1 werden behandeld, was de ORR 45% (95% BI: 24%, 68%) en 30% van de responders had een duurzame respons groter dan of gelijk aan 6 maanden.
Van de 38 patiënten die werden behandeld in studie 2, was de ORR 34% (95% BI: 20%, 51%), waarbij 23% van de patiënten een duurzame respons had van meer dan of gelijk aan 6 maanden. Voor beide onderzoeken werden remissies van de tumoren waargenomen in het bot, het beenmerg of beide.

Wel kan de behandeling met naxitamab gepaard gaan met grote kans op fikse bijwerkingen en wordt ook voor gewaarschuwd in de toelating van de FDA:

De voorschrijfinformatie bevat een Boxed Warning waarin staat dat naxitamab ernstige infusiegerelateerde reacties en neurotoxiciteit kan veroorzaken, waaronder ernstige neuropathische pijn, transverse myelitis en reversibel posterieur leuko-encefalopathiesyndroom (RPLS). Om deze risico's te verkleinen, dienen patiënten premedicatie te krijgen voorafgaand aan elke infusie met naxitamab en nauwkeurig gecontroleerd te worden tijdens en gedurende ten minste twee uur na voltooiing van elke infusie.

De meest voorkomende bijwerkingen (incidentie ≥ 25% in beide onderzoeken) bij patiënten die naxitamab kregen, waren infusiegerelateerde reacties, pijn, verhoogde hartslag, braken, hoesten, misselijkheid, diarree, verminderde eetlust, hypertensie, vermoeidheid, erythema multiforme, perifere neuropathie, urticaria. pyrexie, hoofdpijn, reactie op de injectieplaats, oedeem, angst, lokaal oedeem en prikkelbaarheid. De meest voorkomende laboratoriumafwijkingen van graad 3 of 4 (≥ 5% in beide onderzoeken) waren verminderde lymfocyten, verminderde neutrofielen, verlaagd hemoglobine, verlaagd aantal bloedplaatjes, verlaagd kalium, verhoogd alanineaminotransferase, verlaagd glucose, verlaagd calcium, verlaagd albumine, verlaagd natrium- en verlaagd fosfaat.

Het persbericht van de FDA staat hier:

FDA grants accelerated approval to naxitamab for high-risk neuroblastoma in bone or bone marrow

On November 25, 2020, the Food and Drug Administration granted accelerated approval to naxitamab (DANYELZA, Y-mAbs Therapeutics, Inc.) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) for pediatric patients one year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow demonstrating a partial response, minor response, or stable disease to prior therapy.

Efficacy was evaluated in patients with relapsed or refractory neuroblastoma in the bone or bone marrow enrolled in two single-arm, open-label trials: Study 201 (NCT 03363373) and Study 12-230 (NCT 01757626). Patients with progressive disease following their most recent therapy were excluded. Patients received 3 mg/kg naxitamab administered as an intravenous infusion on days 1, 3, and 5 of each 4-week cycle in combination with GM-CSF subcutaneously at 250 µg/m2/day on days -4 to 0 and at 500 µg/m2/day on days 1 to 5. At the investigator’s discretion, patients were permitted to receive pre-planned radiation to the primary disease site in Study 201 and radiation therapy to non-target bony lesions or soft tissue disease in Study 12-230.

The main efficacy outcome measures were confirmed overall response rate (ORR) per the revised International Neuroblastoma Response Criteria (INRC) and duration of response (DOR). Among 22 patients treated in the multicenter Study 201, the ORR was 45% (95% CI: 24%, 68%) and 30% of responders had a DOR greater or equal to 6 months. Among 38 patients treated in the single-center Study 12-230, the ORR was 34% (95% CI: 20%, 51%) with 23% of patients having a DOR greater or equal to 6 months. For both trials, responses were observed in either the bone, bone marrow or both.

The prescribing information contains a Boxed Warning stating that naxitamab can cause serious infusion-related reactions and neurotoxicity, including severe neuropathic pain, transverse myelitis and reversible posterior leukoencephalopathy syndrome (RPLS). To mitigate these risks, patients should receive premedication prior to each naxitamab infusion and be closely monitored during and for at least two hours following completion of each infusion.

The most common adverse reactions (incidence ≥25% in either trial) in patients receiving naxitamab were infusion-related reactions, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema, and irritability. The most common Grade 3 or 4 laboratory abnormalities (≥5% in either trial) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium and decreased phosphate.

The recommended naxitamab dose is 3 mg/kg/day (up to 150 mg/day) on days 1, 3, and 5 of each treatment cycle, administered after dilution as an intravenous infusion in combination with GM-CSF, subcutaneously at 250 µg/m2/day on days -4 to 0 and at 500 µg/m2/day on days 1 to 5. Treatment cycles are repeated every 4 to 8 weeks.

View full prescribing information for DANYELZA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761171lbl.pdf

naxitamab in combination with GM-CSF may provide a treatment option for patients with relapsed/refractory high-risk neuroblastoma.

Abstract van deze studie is te lezen in PDF. Klik op de titel.

Naxitamab in combination with granulocytemacrophage colony stimulation factor for relapsed/refractory high-risk neuroblastoma

Naxitamab in combination with granulocyte macrophage colony stimulation (GM-CSF) is in clinical development for the treatment of patients with relapsed/refractory high risk neuroblastoma. Neuroblastoma is a rare cancer that mostly affects babies and young children. It develops from specialised nerve cells (neuroblasts) in the foetus that do not become mature nerve cells. Instead, they continue to grow and divide becoming cancerous. Relapsed or refractory high risk neuroblastoma has significant effect on children, young people and their families and carers. Existing treatments and procedures for neuroblastoma are painful and debilitating, with severe and longlasting side effects. Naxitamab is a type of protein that has been designed to recognise and attach to a specific structure called GD2 that is present in high amounts on the surface of neuroblastoma cells, but not normal cells. Naxitamab attaches to the neuroblastoma cells and activates the immune system, which then kills the cancer cells. If licensed, naxitamab in combination with GM-CSF may provide a treatment option for patients with relapsed/refractory high-risk neuroblastoma.