Recurrent Glioblastoma
Conditions
Brief summary
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.
Interventions
* Investigational product (IP): TTAC-0001 and Pembrolizumab (Merck, Keytruda®) * Treatment groups: 3 dose levels * Dose level 1 (optimal starting dose): TTAC-0001 12 mg/kg on D1, D8 and D15 + Pembrolizumab 200 mg on D1 * Dose level 2 (first escalation dose): TTAC-0001 16 mg/kg on D1, D8 and D15 + Pembrolizumab 200 mg on D1 * Dose level 0 (de-escalation dose): TTAC-0001 8 mg/kg on D1, D8 and D15 + Pembrolizumab 200 mg on D1 * Cycle: 3 weeks (21 days per cycle)
Sponsors
PharmAbcine
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This was mTPI design to start with optimal dose and next dose level is selected accroding to DLT occurrance
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose limiting toxicities | During the first cycle (every cycle is 21 days) of treatment | The frequency and percentage of DLT will be presented by dose level |
| Adverse events | From the screening visit to the end of treatment visit (time of progressive disease or 2 years) | The frequency and percentage of AEs will be presented by dose level |
| Immunogenicity | From screening visit to end of treatment visit (time of progressive disease or 2 years) | Presence anti-drug antibody (ADA) will be listed |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate | At every 2nd cycles until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years (every cycle is 21 days) | complete response (CR) or partial response (PR) by RANO criteria |
| Overall survival | From screening visit to date of patient's death (assessed up to 2 year after end of treatment visit) | Period from the date of the drug administration to the patient's death |
| Disease control rate | At every 2nd cycles until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years (every cycle is 21 days) | complete response (CR), partial response (PR) or stable disease (SD) by RANO criteria |
| Progression free survival | From screening visit to end of treatment visit (time of progressive disease or 2 years) | Period from the date of the drug administration to the disease progression time point |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic parameters - T½ | From screening visit to end of treatment visit (time of progressive disease or 2 years) | Half-life by dose level |
| Change in concentration of serum angiogenic factor or receptor | From screening visit to end of treatment visit (time of progressive disease or 2 years) | VEGF, placental growth factor \[PLGF\], soluble vascular endothelial growth factor receptor \[sVEGFR\]-2, sVEGFR-1, etc. |
| Pharmacokinetic parameters - Cmax | From screening visit to end of treatment visit (time of progressive disease or 2 years) | Maximum concentration of drug by dose level |
| PD-L1, VEGFR-2 expression level | From screening visit to end of treatment visit (time of progressive disease or 2 years) | PD-L1, VEGFR-2 expression level in tumour environment such as tumour, tumour vessel and parenchymal tissue |
| DCE-MRI | From screening visit to end of treatment visit (time of progressive disease or 2 years) | Blood flow parameter - iAUC, K-trans |
| Pharmacokinetic parameters - Cmin | From screening visit to end of treatment visit (time of progressive disease or 2 years) | Minimum concentration of drug by dose level |
| Pharmacokinetic parameters - AUC0-t | From screening visit to end of treatment visit (time of progressive disease or 2 years) | Area under the curve from baseline to each timepoint by dose level |
| Pharmacokinetic parameters - Tmax | From screening visit to end of treatment visit (time of progressive disease or 2 years) | Time of Cmax by dose level |
| Pharmacokinetic parameters - CL | From screening visit to end of treatment visit (time of progressive disease or 2 years) | Clearance by dose level |
| Pharmacokinetic parameters - Vd | From screening visit to end of treatment visit (time of progressive disease or 2 years) | Volume of distribution by dose level |
| Pharmacokinetic parameters - Ke | From screening visit to end of treatment visit (time of progressive disease or 2 years) | Elimination rate constant by dose level |
Countries
Australia
Outcome results
None listed