Cambridge Brain Mets Trial 1: A proof of principle phase 1b / randomised phase 2 study of afatinib penetration into cerebral metastases for patients undergoing neurosurgical resection, both with and without prior low-dose, targeted radiotherapy.

Research summary

Brain metastases occur in 20% to 40% of all patients with cancer, with an incidence 10 times higher than that of primary malignant brain tumours. Patients with brain metastases are an underserved population. Overall, they have a poor prognosis with a median survival of 1-2 months with corticosteroids and only 5-7 months after whole-brain radiotherapy. Moreover, the incidence of brain metastases is increasing as a result of more sensitive imaging techniques and longer survival of patients with extracranial metastases.

An important factor in the poor prognosis of patients with brain metastases is the inability of many drugs to penetrate the blood-brain-barrier (BBB) into tumour tissue. A number of strategies have been investigated to help improve this but as yet none of these are being used in routine clinical practice. Combination therapy with surgical excision, radiotherapy and novel drugs could potentially improve the prognosis for some patients, but successful drug delivery across the BBB will be essential.

This is a randomised phase II trial with a phase Ib safety run-in. The initial safety run-in is to assess the safety of afatinib combined with radiotherapy and to identify the maximum dose of afatinib from the planned 20mg, 30mg or 40mg combined with radiotherapy. The aim of randomised phase II is to investigate whether afatinib delivery to brain metastases is enhanced following a single fraction of low-dose, targeted radiotherapy. Afatinib concentration in resected metastases will be measured as the primary outcome measure, using a validated assay.

Main inclusion criteria

  1. Operable brain metastases from likely breast or lung origin as determined by local MDT. Both of the following groups of patients may be considered eligible:

    1. Patients with a past history of histologically/cytologically confirmed breast or lung cancer, now presenting with a new likely brain metastasis from that primary.
    2. Patients presenting with new, primary (breast/lung) tumours, plus synchronous, operable brain metastases, without pre-op tissue diagnosis.
  2. ECOG performance score 0, 1 or 2.
  3. Aged 18 years or older.
  4. Written informed consent.
  5. Patients are allowed to take oral corticosteroids however the plan should be for them to receive a stable dose of corticosteroids for at least 3 days before neurosurgery (i.e. trial days 10, 11, 12)

Main exclusion criteria

The presence of any of the following will preclude patient inclusion:

  1. History or presence of existing interstitial lung disease.

  2. Current clinically significant impairment of cardiac function (greater than Class II according to New York Heart Association [NYHA] classification).

  3. Unstable ischemic heart disease within the last 6 months, including myocardial infarction.

  4. Presence of QTc interval prolongation >480 ms.

  5. Clinically significant corneal or conjunctival eye disease.

  6. Clinically significant skin diseases such as psoriasis, rash or atopic dermatitis.

  7. Clinically significant impairment of GI function or GI disease including total gastrectomy that may alter the absorption of afatinib.

  8. Clinically significant, active peptic ulcer disease.

  9. Known positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody or patients with any untreated serious infections.

  10. Pregnancy and contraception:

    1. Female patients of child bearing potential must have a negative serum or urine pregnancy test within 14 days prior to registration/randomisation and must use an effective method of contraception at least 1 week prior to treatment, during treatment and for at least 28days after the final dose of study drug. Acceptable methods are:

      1. True abstinence (this must be the patients usual and preferred lifestyle, not just for the duration of the study)

      2. Oral contraceptive (either combined or progestogen alone)

      3. Contraceptive implant, injections or patches

      4. Vaginal ring

      5. Intrauterine device (IUD, coil or intrauterine system)

      6. Condom and cap

      7. Diaphragm plus spermicide

      8. Tubal ligation

    2. A female patient of child bearing potential is defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 24 consecutive months if aged 55 years or younger or 12 months if aged 56 years or older.

    3. Men must use one of the following, reliable forms to contraception for the entire duration of treatment and for 28 days after the final dose of study drug:

      1. Condom plus spermicide even if female partner is using another method of contraception (Men should also use a condom to protect male partners, or female partners who are pregnant or breast feeding, from exposure to the study medicine in semen).

      2. True abstinence (this must be the patients usual and preferred lifestyle, not just for the duration of the study)

  11. Concurrent severe and/or uncontrolled medical conditions (due to concurrent disease other than cancer) which in the opinion of the investigator could compromise participation in the study.

  12. Known or suspected active drug or alcohol abuse.

  13. Administration of chemotherapy, immunotherapy, radiotherapy or any investigational cancer therapy within 5 half-lives of the prior therapy, or 2 weeks of first dose of afatinib, whichever is longer. Continuation of established endocrine therapy is allowed and no washout period is required. Established endocrine therapy (which may include GnRH analogues) is that which has been administered for at least 2 weeks prior to starting afatinib on Day 1.

  14. Known hypersensitivity to afatinib or its excipients.

  15. Toxicities of prior therapies that have not resolved to ≤CTCAE Grade 1.

  16. Any of the following laboratory test findings:

    1. Haemoglobin <90 g/L

    2. Absolute neutrophil count <1 x 109 /L

    3. Platelet count <100 x 109 /L

    4. AST or ALT >2.5 x upper limit of normal range (ULN)

    5. Total serum bilirubin >1.5 x ULN

    6. Creatinine >1.5 x ULN

    7. Creatinine clearance <30mL/min (Cockcroft-Gault)

  17. Patients taking potent P-gp inducers/inhibitors (see section 15.9)

  18. Any other reason which, in the opinion of the Investigator, interferes with the ability of the patient to participate in the study.

  19. Patients unable to comply with the protocol.

Chief investigator

Dr Richard Baird

Contact details

Cancer Theme Email: [email protected]