This will be a single-arm open-label prospective pilot feasibility trial recruiting 10 adult patients with recurrent glioblastoma who are assigned to receive the personalized study treatment based on the genetic profile of their recurrent GBM tumor resected at the time of surgery. It will be aimed to gather preliminary information on the study intervention and the feasibility of conducting a full-scale trial.

Inclusion Criteria:

1. Study participant has provided informed consent prior to initiation of any study specific activities/procedures.

2. Adult participants, male and female, aged ≥18 who have a pathologically confirmed IDH-wild type glioblastoma, with first or second progression of the tumor, after initial treatment with radiation therapy and temozolomide.

3. Recurrence is amenable to resection.

4. Performance status: ECOG ≤2.

5. Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test at the time of screening. WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy or bilateral salpingectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes.

6. Patients of childbearing potential must adhere to the contraception requirement from screening throughout the study period up to 180 days after the last dose of study intervention. Women/men of childbearing potential must have agreed to use two highly effective contraceptive methods. In addition to routine contraceptive methods such as condom use, oral contraceptive, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.

   Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard.

7. Able to undergo brain MRIs.

8. Females must not be breastfeeding, throughout the study period up to 180 days after the last dose of study intervention.

9. Male patients should agree to not donate sperm during the study for at least 6 months until discontinuation of study drug.

Exclusion Criteria:

1. Patients with history of abnormal left ventricular ejection fraction (LVEF≤ 45%).

2. Pregnant, breast-feeding, unwilling/unable to comply with contraception requirements.

3. Patients unable to consent.

4. Abnormal (grade ≥2 CTCAE, version 5.0) laboratory values for hematology, renal, and liver function including:

   1. Hemoglobin <10,
   2. Neutrophils <1.5,
   3. Platelets <75,
   4. ALT/AST >3x ULN,
   5. Bilirubin >1.5 x ULN,
   6. eGFR <60

5. Patients with significant or recent gastrointestinal disorders with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption or severe diarrhea of any etiology) must be excluded from the clinical trial (Afatanib is not recommended in this patient population).

6. Patients with a history of ILD (interstitial lung disease) must be excluded.

7. Patients with severe hepatic impairment (Child Pugh C).

8. A significantly abnormal ECG (baseline QTcF interval > 450 msec).

9. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

10. Patients with known pre-existing pleural effusion.

11. Active hepatitis B or C infection and/or known history of HIV infection.

12. Has known psychiatric or substance abuse disorders that would interfere with compliance with the requirements of the trial.

13. Subject will not be available for protocol-required study visits or procedures, to the best of the subject's and investigator's knowledge.

14. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks from the date of signing the informed consent form.

15. Patients who are hypersensitive to any ingredients in the formulation of the study drugs or their excipients.

16. Patients receiving active treatment for a different cancer.

17. If recent bacterial infection, patients need to have completed antibiotic course prior to commencing study drug.

18. If recent COVID-19 infection, patients must have recovered from it prior to commencing study drug.

19. Patients on strong CYP3A/p-gp inducers (for example, carbamazepine and phenytoin).

N.B. Only patients receiving SOC neurosurgery in Alberta, Canada are eligible to participate in this trial.