TTAC-0001 and Pembrolizumab Combination phase1b Trial in Recurrent Glioblastoma

A Phase 1b, Open-Label, Safety and Tolerability Study of TTAC-0001 in Combination With Pembrolizumab in Patients With Recurrent Glioblastoma

This is a phase 1b, open-Label clinical trial to determine the safety and tolerability and to establish a preliminary recommended Phase 2 dose (RP2D) of TTAC-0001 administered in combination with pembrolizumab in patients with recurrent glioblastoma.

Inclusion Criteria:

1. Diagnosed with primary glioblastoma by histopathological examination and confirmed recurrent glioblastoma by magnetic resonance imaging (MRI) scans after completing standard of care (Stupp protocol) concomitant temozolomide chemotherapy with radiotherapy (CCRT)

2. At least one confirmed measurable lesion by RANO criteria

3. Karnofsky Performance Status (KPS) ≥80

4. A person who satisfies the following criteria in haematologic, renal, and hepatic function tests performed within 7 days prior to screening:

   1. Haematologic tests

      • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
      • Platelets ≥ 100 x 109/L
      • Haemoglobin ≥ 9.0 g/dL

   2. Blood coagulation tests

      • Prothrombin time (PT) ≤ 1.5 x Upper limit of normal (ULN)
      • Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN

   3. Hepatic function tests

      • Total bilirubin ≤ 1.5 x UNL
      • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastasis)

   4. Renal function test

      • ≤1.5 × ULN or creatinine clearance (CrCl) ≥30 mL/min for patient with creatinine levels >1.5 × institutional ULN

5. At least 12 weeks of expected survival time

6. The patient (or legally acceptable representative if applicable) is able and willing to provide written informed consent for the trial

Exclusion Criteria:

1. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. (Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ [e.g., breast carcinoma, cervical cancer in situ] controlled by curative therapy are not excluded)
2. Has received prior radiotherapy within 2 weeks of start of study treatment. Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease
3. Has a history of (non-infectious) pneumonitis/interstitial lung diseases that required steroids or current pneumonitis/interstitial lung disease
4. Has an active infection requiring systemic therapy
5. Uncontrolled hypertension (systolic blood pressure [SBP]> 150 or diastolic blood pressure [DBP]> 90 mmHg)
6. Uncontrolled seizures
7. Class III or IV heart failure by New York Heart Association (NYHA) classification
8. Has oxygen-dependent chronic disease
9. Active psychiatric disorder (schizophrenia, major depressive disorder, bipolar disorder etc.). Treated depression with ongoing antidepressant medication is not an exclusion
10. History of abdominal fistula or gastrointestinal perforation within 6 months prior to start of study drug
11. History of serious gastrointestinal haemorrhage within 6 months prior to start of study drug
12. History of severe arterial thromboembolic event within 12 months of start of study drug
13. Serious grade 4 venous thromboembolic event including pulmonary embolism
14. History of hypertensive crisis or hypertensive encephalopathy
15. History of posterior reversible encephalopathy syndrome
16. Planned surgery within 4 weeks post last dose
17. Moderate to severe proteinuria as demonstrated by urine dipstick for proteinuria ≥2+. For patients with ≥2+ proteinuria on dipstick urinalysis, a urine protein: creatinine (UPC) ratio will be determined, or a 24-hour urine collection will be done. Patients with a UPC ratio <1 or a 24-hour urine protein <1 gram are eligible
18. Requiring therapeutic anticoagulation with warfarin at baseline; patients must be off warfarin or warfarin-derivative anticoagulants for at least 7 days prior to starting study drug; however, therapeutic or prophylactic therapy with low-molecular weight heparin is allowed
19. Not recovered below National Cancer Institute-Common Terminology for Adverse Events (NCI-CTCAE) grade 1 or baseline from AEs due to previous therapy (patient with ≤ Grade 2 neuropathy or alopecia may be eligible)
20. Treatment with systemic chemotherapy, hormonal therapy, immunotherapy or biologic therapy within 2 weeks prior to the baseline visit
21. Undergone major surgery requiring general anaesthesia or a respiratory assistance device within 4 weeks prior to the baseline visit (within 2 weeks for video-assisted thoracoscopic surgery [VATS] or open-and-closed [ONC] surgery)
22. Treated with other investigational drugs within 4 weeks prior to the baseline visit for this study
23. Pregnant* or lactating females, and females/males of childbearing potential who do not agree to a reliable and adequate method of contraception
24. A known history of severe drug hypersensitivity or hypersensitivity to a therapy similar to the study drugs
25. Unable to participate in the trial according to the investigator's decision
26. Previous therapy with vascular endothelial growth factor (VEGF)-targeted agents including (but not limited to) bevacizumab
27. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher irAE
28. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
29. Known human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
30. Known active hepatitis B or hepatitis C infection. No testing for hepatitis B and hepatitis C is required unless mandated by local health authority
31. Have received a live vaccine within 30 days prior to enrollment. Seasonal flu vaccines that do not contain live virus are permitted
32. Have had a serious or non-healing wound, ulcer, or bone fracture within 28 days prior to enrollment