Study of safety and efficacy of Betalutin & rituximab in pts with FL
Research type
Research Study
Full title
A phase 1b open-label study of Betalutin in combination with rituximab in patients with relapsed/refractory follicular lymphoma (Archer-1)
IRAS ID
242580
Contact name
Matthew Beasley
Contact email
Sponsor organisation
Nordic Nanovector ASA
Eudract number
2017-004506-18
Duration of Study in the UK
6 years, 8 months, 31 days
Research summary
Research Summary
Indolent Non-Hodgkin lymphoma (iNHL) remains largely incurable, and nearly all patients relapse. As patients relapse, they become resistant or refractory to commonly used therapies, including rituximab (RTX) and alkylating agents, and their prognosis worsens, especially for those who are no longer able to tolerate chemotherapy. New therapies with different mechanisms of action are thus needed to improve outcomes in patients who have recurrent NHL following Rituximab or other anti-CD20-based therapy.
This is a Phase 1b, open-label, single arm dose escalation study of Betalutin followed by RTX in patients with previously treated Follicular Lymphoma (FL). The aim is to investigate the activity and safety of Betalutin combined with RTX in patients with FL who have received one or more prior therapies in 20-25 patients.
All patients will receive a single i.v. dose of RTX (375 mg/m2) on day -14, and then sequential iv administration of lilotomab (40 mg) followed by Betalutin (10 or 15 MBq/kg) within 4 hours on Day 0. Patients will then be administered RTX (375 mg/m2) i.v. on Days 7, 14, 21 and 28.
Two cohorts of 3-6 patients will be initially evaluated for dose limiting toxicity, in a 3+3 escalation pattern, before determining the subsequent Betalutin/lilotomab dose for the remainder of the study.
Patients will undergo assessments during screening/baseline and periodically during treatment. PET/CT and CT (or MRI) imaging will be done at baseline, 3 and 6 months. CT (or MRI) with contrast will be performed at 12, 18, 24 months and then yearly until disease progression or for a maximum of 5 years after Betalutin administration for all patients.
Patients who achieve Stable Disease, Complete Response or Partial Response on their month 3 imaging scan will be administered maintenance RTX 375 mg/m2 i.v. or 1400 mg s.c. every 3 months for up to 2 years, or until disease progression.Summary of Results
When was the study done?
This study started in October 2018 and ended in July 2022.Why was the study done?
Non-Hodgkin’s lymphoma is a type of blood cancer that affects white blood cells called lymphocytes. White blood cells are part of the body's immune system. They help the body fight infection and other diseases. One form of Non-Hodgkin’s lymphoma is called “follicular lymphoma”. Follicular lymphoma is usually treated with chemotherapy and/or immunotherapy (a type of cancer treatment that helps your immune system fight cancer). In some cases, chemotherapy and/or immunotherapy may not be effective against this cancer (called “refractory”) or the cancer may return after the treatment initially works (called “relapse”). Currently, there are not many treatments available for relapsed or refractory follicular lymphoma, particularly for elderly patients, and there is therefore a need for new types of treatment. One standard immunotherapy given for follicular lymphoma is called rituximab. Rituximab is a “monoclonal antibody” and is designed to recognise tumour cells. It may be given alone or combined with other treatments. Radioimmunotherapy is a combination of immunotherapy and radiation therapy that is used to treat follicular lymphoma and some other cancers. Monoclonal antibodies are combined with a radioactive material; the monoclonal antibody binds specifically to the tumour cell, allowing a high dose of radiation to be delivered directly to the tumour cell with the aim of killing the cancer cells while the normal cells are minimally affected.The researchers were looking for a way to treat people with relapsed or refractory follicular lymphoma who had already tried standard treatment, but it did not work for them. They have developed a radioimmunotherapy called Betalutin® in which the radioisotope (a particle that emits radiation) lutetium-177 is attached to an antibody known as lilotomab that recognises lymphocytes involved in follicular lymphoma. Before the Betalutin injection, participants are also given lilotomab on its own (without the radioisotope) to improve the effect of Betalutin on cancer cells. As patients with relapsed/refractory follicular lymphoma may benefit from long-term rituximab treatment, all participants also received rituximab for at least 4 weeks and up to 2 years after Betalutin injection. Before any treatment can be approved for people to take, researchers do clinical studies to find out if it works and to identify any safety concerns.
What was the main objective of the study?
In this study, researchers looked at how this treatment works in the human body. Researchers did medical tests on men and women who have follicular lymphoma before and after they took the treatment. The researchers wanted to find the highest dose of treatment that people could safely be given when combined with rituximab treatment. The researchers wanted to know if there were: • Any unwanted side effects • Any chemical changes in blood or urine In this study, researchers also gave the treatment to find out if it could improve or cure follicular lymphoma.Who took part in the study?
This study included adults living with follicular lymphoma. To be able to take part, participants must have:
• Been at least 18 years old
• Been diagnosed with follicular lymphoma that was confirmed by examination of tissue using a microscope • Had between one and three previous treatments of a particular type for their follicular lymphoma and were either refractory to treatment or they had relapsed again afterwards • Had a life expectancy of at least 3 months Participants were not allowed to be in the study if they had received either of the following:
• A bone marrow transplant
• Any follicular lymphoma treatment in the previous 4 weeks The study included seven participants, six in Norway and one in the Czech Republic. Three (43%) participants were men and four (57%) were women. The participants were born between 1945 and 1973.What treatments did the participants take?
The treatment for all participants was Betalutin, given once as an injection. Participants were also given lilotomab once as an infusion up to 4 hours before the Betalutin injection. A standard dose of rituximab was initially given approximately 2 weeks before Betalutin. As patients with relapsed/refractory follicular lymphoma may benefit from long-term rituximab treatment, all participants also received standard doses of rituximab every week for the first 4 weeks after Betalutin injection and if their disease had improved after 3 months they continued to receive rituximab treatment every 3 months for up to 2 years.
The dose of Betalutin was measured in MegaBequerel, which is a unit of radioactivity. The study had two groups, one group was given 10 MegaBequerel Betalutin and the second group was given 15 MegaBequerel Betalutin, both with 40 mg lilotomab.
This was an “open-label” study. This means each participant knew what the treatment was, and the doctors and study staff also knew.What were the overall results from the study?
No participants reported a side effect considered to be a possible limitation for tolerating Betalutin given in combination with rituximab. Based on the overall safety information, the researchers determined that the dose that could be safely given to participants in further studies was 15 MegaBequerel Betalutin with 40 mg lilotomab and the standard dose of rituximab.
The researchers also measured the size of each tumour to see if it had shrunk, stayed the same, or grew over a 2 year period. Participants finished the study when their tumour grew or if they started another follicular lymphoma treatment. The study staff contacted them by telephone afterwards to find out if they were still alive.
All of the seven participants had tumours that had either shrunk or disappeared when measured after 3 months or 6 months. Three participants had tumours that grew in the 2 years after Betalutin treatment but all participants were still alive at the end of the study.What side effects happened during the study?
Side effects are medical events (such as headache) that happen during the study and are reported because the study doctor believes that they might be related to the treatments in the study (rituximab, lilotomab or Betalutin). A side effect is considered “serious” if it results in death, is a life-threatening condition, is considered to bemedically important by the study doctor, causes long-term problems, needs hospital care or makes current hospital care longer.Did any participants have serious side effects?
One participant had a serious side effect of skin infection that the study doctor thought may be caused by rituximab treatment.Did any participants have non-serious side effects?
Five (71%)of the participants had non-serious side effects. Two participants had a drop in platelets (the cells in the blood that help clotting) and two had a drop in neutrophils (a type of white blood cells that take part in the body’s immune response). One participant had each of the following: drop in white blood cells, palpitations (racing, pounding or fluttering heart), diarrhoea, feeling sick, being sick, tiredness, flu-like symptoms, chest pain, rash with pus inside, allergic reaction to the study treatment, restless leg syndrome (urge to move the legs), cough, nose bleed and skin redness.How has this study helped researchers?
This study has helped researchers start to learn about Betalutin as a possible combination treatment with rituximab for people living with relapsed or refractory follicular lymphoma.
New studies with Betalutin and rituximab for people living with follicular lymphoma are not currently planned. Further studies may be performed in the future.REC name
HSC REC A
REC reference
19/NI/0032
Date of REC Opinion
15 Mar 2019
REC opinion
Further Information Favourable Opinion