A Phase II Stydy of Bevacizumab Plus Erlotinib in Patients for Krebs Cycle Altered Cancer

Inclusion Criteria:

1. Signed and dated informed consent of document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the KOSMOS-II master trial
2. Age 19 or more
3. Histologically confirmed solid cancer
4. Genetic alteration in genes related to Krebs cycle (fumarate hydratase, succinate dehydrogenase, isocitrate dehydrogenase, or maleate dehydrogenase 2). Only pathogenic and likely pathogenic variant in either germline or somatic gene will be permitted.
5. Patients with locally advanced, recurrent, or metastatic disease not amenable to surgery, radiotherapy, or combined modality therapy with curative intent
6. Disease progressed during or after standard treatment with no further treatment option, no standard treatment, patient's refusal to receive standard treatment, or unfit for standard treatment. If standard treatment contains bevacizumab and/or erlotinib, patient can be included according to treating physician's discretion
7. Measurable disease according to RECIST v1.1 criteria
8. ECOG performance status 0 or 2
9. Adequate bone marrow, hepatic, and renal function Hematology

   * Neutrophil \>= 1,500/mm3
   * Platelet \>= 100,000/mm3
   * Hemoglobin \>= 9 g/dL Liver function tests
   * Total bilirubin ≤ 1.5 xULN
   * AST, ALT ≤ 3 xULN (in case of liver metastasis, 5 x upper limit of normal) Renal function tests
   * Creatinine clearance \>= 30 mL/min
10. Life expectancy more than 3 months
11. Signed and dated informed consent of document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrollment

Exclusion Criteria:

1. Previous treatment with combination of vascular endothelial growth factor inhibitors and epithelial growth factor receptor inhibitors. Previous exposure to only VEGF inhibitor or EGFR inhibitor, or sequential exposure to both agents can be included at the treating physician's discretion
2. Previous radiotherapy to the only measurable lesion: but previous radiotherapy will be permitted unless the lesion is the only measurable lesion
3. Uncontrolled CNS metastasis (brain and/or leptomeningeal metastasis) that requires anti-edema drugs such as steroid for symptoms or symptom management. Primary CNS malignancy such as glioblastoma can be included by treating physician's discretion.
4. Have clinically problematic cardiovascular diseases, such as unstable angina, congestive heart failure, advanced arrhythmia requiring treatment with medication, or a history of myocardial infarction within 12 months prior to enrollment. Inclusion is allowed if patient has no evidence of active disease for at least 6 months prior to enrollment.
5. Inadequately controlled hypertension (systolic blood pressure \> 150 mmHg or diastolic pressure \> 100 mmHg on anti-hypertensive medications).
6. History of cerebral vascular accident (CVA) or transient ischemic attack (TIA) ≤ 6 months prior to screening
7. History of bleeding diathesis or coagulopathy
8. Urine dipstick proteinuria≥2+ or urine protein/creatinine ratio \>1.0. If patients are discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ 1g of proteinuria in 24 hours.
9. Currently on maximal dose of therapeutic anticoagulation for thromboembolic disease.
10. Clinically significant bleeding (hemoptysis, melena, hematochezia, tumor bleeding, etc.), or at risk of significant bleeding (tumor infiltrating into the great vessels or an evident cavitation of cancer lesions)
11. Have any of the following gastrointestinal disturbances.

    * Unable to take internal medications ② Required intravenous feeding ③ Have malabsorption due to surgical treatment (such as gastrointestinal resection) or underlying disease ④ Have an active peptic ulcer (enrollment is permitted if the patient is being given prophylactic treatment for a previous condition or treatment for complications from gastritis, etc.) ⑤ History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess ≤ 6 months prior to screening
12. Serious non-healing wound, ulcer, bone fracture or have undergone a major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior to screening.
13. Diagnosis of any serious secondary malignancy within the last 2 years, except for adequately treated basal cell or squamous cell carcinoma of skin, or in situ carcinoma of cervix uteri or prostate cancer and curatively treated thyroid cancer of any stage.
14. Pregnancy or breast feeding
15. Men or women who are not intending to use contraceptive methods during the study period.
16. Major surgery is scheduled during the study period
17. Other severe acute or chronic medical or psychiatric condition
18. Individuals who are deemed to be unsuitable for participation in this study by the investigators for any other reason
19. Where participation in this clinical trial is not appropriate in the judgment of the investigator for any other reason