A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma
John de Groot,
Martina Ott,
Jun Wei,
Cynthia Kassab,
Dexing Fang,
Hinda Najem,
Barbara O'Brien,
Shiao-Pei Weathers,
Carlos Kamiya Matsouka,
Nazanin K Majd,
Rebecca A Harrison,
Gregory N Fuller,
Jason T Huse,
James P Long,
Raymond Sawaya,
Ganesh Rao,
Tobey J MacDonald,
Waldemar Priebe,
Michael DeCuypere,
Amy B Heimberger
Affiliations
John de Groot
1Departments of Neurology & Neurosurgery, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA 94143, USA
Martina Ott
2Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Jun Wei
2Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Cynthia Kassab
2Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Dexing Fang
2Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Hinda Najem
3Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, 259 E Erie St, Chicago, IL 60611, USA
Barbara O'Brien
5Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Shiao-Pei Weathers
5Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Carlos Kamiya Matsouka
5Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Nazanin K Majd
5Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Rebecca A Harrison
5Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Gregory N Fuller
6Department of Neuropathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Jason T Huse
6Department of Neuropathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
James P Long
7Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Raymond Sawaya
2Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Ganesh Rao
2Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Tobey J MacDonald
8Department of Pediatrics, Emory University School of Medicine, Aflac Cancer & Blood Disorders Center of Children's Healthcare of Atlanta, 1405 Clifton Road NE, Atlanta, GA 30322, USA
Waldemar Priebe
9Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Michael DeCuypere
3Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, 259 E Erie St, Chicago, IL 60611, USA
Amy B Heimberger
3Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, 259 E Erie St, Chicago, IL 60611, USA
Aim: To ascertain the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066 and p-STAT3 target engagement within recurrent glioblastoma (GBM) patients. Patients & methods: In a first-in-human open-label, single-center, single-arm 3 + 3 design Phase I clinical trial, eight patients were treated with WP1066 until disease progression or unacceptable toxicities. Results: In the absence of significant toxicity, the MFD was identified to be 8 mg/kg. The most common adverse event was grade 1 nausea and diarrhea in 50% of patients. No treatment-related deaths occurred; 6 of 8 patients died from disease progression and one was lost to follow-up. Of 8 patients with radiographic follow-up, all had progressive disease. The longest response duration exceeded 3.25 months. The median progression-free survival (PFS) time was 2.3 months (95% CI: 1.7 months-NA months), and 6-month PFS (PFS6) rate was 0%. The median overall survival (OS) rate was 25 months (95% CI: 22.5 months-NA months), with an estimated 1-year OS rate of 100%. Pharmacokinetic (PK) data demonstrated that at 8 mg/kg, the T1/2 was 2–3 h with a dose dependent increase in the Cmax. Immune monitoring of the peripheral blood demonstrated that there was p-STAT3 suppression starting at a dose of 1 mg/kg. Conclusion: Immune analyses indicated that WP1066 inhibited systemic immune p-STAT3. WP1066 had an MFD identified at 8 mg/kg which is the target allometric dose based on prior preclinical modeling in combination with radiation therapy and a Phase II study is being planned for newly diagnosed MGMT promoter unmethylated glioblastoma patients.
