TTAC-0001 and Pembrolizumab Combination phase1b Trial in Recurrent Glioblastoma

Recurrent Glioblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03722342
• Other study ID #: PMC_TTAC-0001_04
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: January 16, 2019
• Est. completion date: September 30, 2022

Study information

• Verified date: August 2022
• Source: PharmAbcine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 9
• Est. completion date: September 30, 2022
• Est. primary completion date: November 4, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Glioblastoma
• Recurrence
• Recurrent Glioblastoma

Intervention

Drug:
• TTAC-0001 and pembrolizumab combination
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)

Locations

Country	Name	City	State
Australia	Austin Hospital	Heidelberg	Victoria
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia

Sponsors (1)

Lead Sponsor	Collaborator
PharmAbcine

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pharmacokinetic parameters - Cmax	Maximum concentration of drug by dose level	From screening visit to end of treatment visit (time of progressive disease or 2 years)
Other	Pharmacokinetic parameters - Cmin	Minimum concentration of drug by dose level	From screening visit to end of treatment visit (time of progressive disease or 2 years)
Other	Pharmacokinetic parameters - AUC0-t	Area under the curve from baseline to each timepoint by dose level	From screening visit to end of treatment visit (time of progressive disease or 2 years)
Other	Pharmacokinetic parameters - Tmax	Time of Cmax by dose level	From screening visit to end of treatment visit (time of progressive disease or 2 years)
Other	Pharmacokinetic parameters - CL	Clearance by dose level	From screening visit to end of treatment visit (time of progressive disease or 2 years)
Other	Pharmacokinetic parameters - Vd	Volume of distribution by dose level	From screening visit to end of treatment visit (time of progressive disease or 2 years)
Other	Pharmacokinetic parameters - Ke	Elimination rate constant by dose level	From screening visit to end of treatment visit (time of progressive disease or 2 years)
Other	Pharmacokinetic parameters - T½	Half-life by dose level	From screening visit to end of treatment visit (time of progressive disease or 2 years)
Other	Change in concentration of serum angiogenic factor or receptor	VEGF, placental growth factor [PLGF], soluble vascular endothelial growth factor receptor [sVEGFR]-2, sVEGFR-1, etc.	From screening visit to end of treatment visit (time of progressive disease or 2 years)
Other	DCE-MRI	Blood flow parameter - iAUC, K-trans	From screening visit to end of treatment visit (time of progressive disease or 2 years)
Other	PD-L1, VEGFR-2 expression level	PD-L1, VEGFR-2 expression level in tumour environment such as tumour, tumour vessel and parenchymal tissue	From screening visit to end of treatment visit (time of progressive disease or 2 years)
Primary	Dose limiting toxicities	The frequency and percentage of DLT will be presented by dose level	During the first cycle (every cycle is 21 days) of treatment
Primary	Adverse events	The frequency and percentage of AEs will be presented by dose level	From the screening visit to the end of treatment visit (time of progressive disease or 2 years)
Primary	Immunogenicity	Presence anti-drug antibody (ADA) will be listed	From screening visit to end of treatment visit (time of progressive disease or 2 years)
Secondary	Overall response rate	complete response (CR) or partial response (PR) by RANO criteria	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)
Secondary	Disease control rate	complete response (CR), partial response (PR) or stable disease (SD) by RANO criteria	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)
Secondary	Progression free survival	Period from the date of the drug administration to the disease progression time point	From screening visit to end of treatment visit (time of progressive disease or 2 years)
Secondary	Overall survival	Period from the date of the drug administration to the patient's death	From screening visit to date of patient's death (assessed up to 2 year after end of treatment visit)