Clinical Trials /

AflacST1901: Peds WP1066

NCT04334863

Description:

In this Phase I clinical study, the investigators plan to offer investigational treatment with the novel JAK2/STAT3 inhibitor WP1066 (Moleculin Biotech, Inc.) to pediatric patients with any progressive or recurrent malignant brain tumor that is refractory to standard treatment and is without known cure.

Related Conditions:
  • Malignant Brain Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: AflacST1901: Peds WP1066
  • Official Title: A Phase I Study of WP1066 in Children With Refractory and Progressive or Recurrent Malignant Brain Tumors

Clinical Trial IDs

  • ORG STUDY ID: IRB00113194
  • NCT ID: NCT04334863

Conditions

  • Brain Tumor
  • Medulloblastoma
  • Brain Metastases

Interventions

DrugSynonymsArms
WP1066STAT3 Inhibitor WP1066WP1066

Purpose

In this Phase I clinical study, the investigators plan to offer investigational treatment with the novel JAK2/STAT3 inhibitor WP1066 (Moleculin Biotech, Inc.) to pediatric patients with any progressive or recurrent malignant brain tumor that is refractory to standard treatment and is without known cure.

Detailed Description

      The goal of this clinical research study is to find the highest tolerable dose of WP1066 that
      can be given to pediatric patients with recurrent (has returned after treatment) cancerous
      brain tumors or melanoma that has gotten worse and spread to the brain. The safety of this
      drug will also be studied.

      WP1066 is designed to target the STAT3 pathway in cancer cells, which makes these cells
      divide, increases new blood vessels to the tumor, causes the cancer cells to move throughout
      the body and brain, and avoids them being detected by the immune system. Targeting this
      pathway may cause the immune system to kill the cancer cells. The investigators will
      administer five escalating doses of WP1066, starting at lowest dose currently found to be
      safe and tolerable in adults.

      WP1066 is not FDA approved or commercially available. It is currently being used for research
      purposes only.

      Up to 36 participants will be enrolled in this study. All will take part at Children's
      Healthcare of Atlanta (CHOA).
    

Trial Arms

NameTypeDescriptionInterventions
WP1066ExperimentalThere will be 5 groups based on the enrollment timing. The first group of participants will receive the lowest dose level of WP1066. Each subject within a group will receive an assigned dose of the investigational drug. The dose levels are 4, 6, 8, 12, and 16 mg/kg of the investigational drug given twice a day. The first group will receive the lowest dose level, 4mg/kg twice a day, and subsequent groups will escalate to the next higher dose level. All groups will be treated identically, except for the dose of drug administered, with the liquid formulation of the drug.
  • WP1066

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed progressive medulloblastoma, malignant
             glioma or any other recurrent/progressive malignant brain tumor, for which curative
             measures do not exist. Primary spinal tumors are eligible. DIPG does not require
             histological confirmation.

          -  Patients must have previously undergone standard-of-care treatment including surgery,
             radiation, and/or first line adjuvant chemotherapy prior to the experimental treatment
             (WP1066).

          -  Patients must have recovered from the acute treatment related toxicities (defined as <
             grade 1 if not defined in eligibility criteria) of all prior chemotherapy,
             immunotherapy or radiotherapy prior to entering this study. There is no upper limit to
             the number of prior therapies that is allowed.

          -  Age 3 to 25 years.

          -  Karnofsky or Lansky Performance Scale score > 60%

          -  Patients must have normal organ and marrow function as defined below:

               -  Absolute neutrophil count > 1,000/mcL

               -  Platelets > 100,000/mc

               -  Total bilirubin within normal institutional limits

               -  AST(SGOT)/ALT(SGPT) < 5 x (<10 x if taking steroids) institutional upper limit of
                  normal

               -  creatinine within normal institutional limits for age, or, creatinine clearance >
                  60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal

               -  PT/PTT < 1.5 x normal institutional standard

          -  Patients with stable seizures (e.g., no seizures for ≥ 14 days and not requiring
             escalation or addition of anti-epileptic drugs) will be eligible.

          -  Signed informed written consent obtained from patient if 18 years of age or older, or
             from guardian/legal representative if patient is less than 18 years of age.

        Exclusion Criteria:

          -  Patients must have received their last dose of known myelosuppressive anticancer
             therapy at least three (3) weeks prior to study enrollment or at least six (6) weeks
             if prior nitrosourea.

          -  Biologic or investigational agent (anti-neoplastic): Patient must have received their
             last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment.

          -  Antibodies: ≥ 21 days must have elapsed from infusion of last dose of antibody, and
             toxicity related to prior antibody therapy must be recovered to Grade ≤ 1. Agents with
             prolonged half-lives: At least three half-lives must have elapsed prior to enrollment.

          -  Immunotherapy: Patient must have completed immunotherapy (e.g. tumor vaccines,
             oncolytic viruses. etc.) at least 42 days prior to enrollment.

          -  Radiation: Patients must have had their last fraction of: •Craniospinal irradiation ≥
             3 months prior to enrollment. •Other substantial bone marrow irradiation ≥ 6 weeks
             prior to enrollment •Local palliative XRT (small port) ≥ 2 weeks.

          -  Stem Cell Transplant: Patient must be ≥ 12 weeks since autologous bone marrow/stem
             cell transplant prior to enrollment.

          -  Surgery Patients must be fully recovered from all acute effects of prior surgical
             intervention.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to WP1066.

          -  The enzymatic metabolism profile of WP1066 is unknown. Patients who are receiving
             drugs that significantly interact with the CYP450 enzyme(s) are ineligible. However,
             if they are switched to other medications with a 2-week washout window, they will be
             eligible. Patients are also excluded if they have been exposed within 7 days of
             planned first study treatment day to medications that are predominantly CYP2D6, 2C9 or
             2C19 substrates, strong inhibitors or inducers, and sensitive substrates of CYP3A4
             with narrow therapeutic range.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  No single lesion can be larger than 5 cm in maximal diameter. There may not be
             clinically significant midline shift or hydrocephalus.

          -  The effects of WP1066 on the developing human fetus are unknown. Pregnant women are
             excluded from this study because WP1066 could potentially be teratogenic or have
             abortifacient effects. Because there is an unknown but potential risk for adverse
             events in nursing infants secondary to treatment of the mother with WP1066,
             breastfeeding should be discontinued if the mother is treated with WP1066. Female
             subjects of childbearing potential should be willing to use 2 methods of birth control
             prior to study entry, during the study, and for 2 months after the last dose of the
             study drug or be surgically sterile. Subjects of childbearing potential are those who
             have not been surgically sterilized or have not been free from menses for > 1 year.
             Should a woman become pregnant or suspect she is pregnant while she or her partner is
             participating in this study, she should inform her treating physician immediately. Men
             treated or enrolled on this protocol must also agree to use adequate contraception
             prior to the study, for the duration of study participation, and 4 months after
             completion of WP1066 administration.

          -  HIV-positive patients receiving combination antiretroviral therapy are ineligible
             because of the potential for pharmacokinetic interactions with WP1066.

          -  The potential for further hemorrhaging with the use of WP1066 is unknown. It will be
             at the PIs discretion to enroll a patient who has a small, asymptomatic brain
             hemorrhage, but patients who have had symptomatic hemorrhages will be excluded.

          -  Patients requiring escalation of the corticosteroid dose will be excluded, but
             patients receiving a stable or decreasing dose for at least one week prior to
             registration will be eligible.

          -  The cardiac toxicities of WP1066 are unknown. Thus, patients who have a mean QTc
             interval >450 ms at baseline will be excluded. Concomitant use of agents that prolong
             the QT interval will be avoided.

          -  Patients with uncontrolled seizures or seizure requiring escalation or addition of
             anti-epileptic drugs will be excluded.

          -  The use of medical cannabis and CBD oil is prohibited during the first 2 cycles of
             this protocol. Patients must be off cannabis oil for 3 days prior to enrollment.
      
Maximum Eligible Age:25 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of WP1066
Time Frame:28 Days post-intervention
Safety Issue:
Description:Maximum tolerated dose (MTD) of WP1066 in pediatric patients with recurrent or refractory and progressive malignant brain tumors for which there is no known treatment with clinical benefit. Maximum tolerated dose (MTD) is determined as the dose level at which 0/6 or 1/6 patients experience a dose-limiting toxicity (DLT) with at least 2 patients experiencing DLT at the next higher dose level. DLT is defined as an adverse event or an abnormal laboratory value assessed as being at least possibly related to the investigational agent that occurs during the first 28 days after administration of the first dose of WP1066.

Secondary Outcome Measures

Measure:Pharmacokinetic of WP1066: Peak plasma concentration (Cmax)
Time Frame:Days 1, 2, 14, and 15 of course 1
Safety Issue:
Description:Cmax is the observed maximum plasma concentration following drug administration. Individual plasma concentration-time data for WP1066 will be used to generate pharmacokinetic parameter estimates using both compartmental and non-compartmental methods.
Measure:Pharmacokinetic of WP1066: Time to peak concentration (Tmax)
Time Frame:Days 1, 2, 14, and 15 of course 1
Safety Issue:
Description:Tmax is the time to reach maximum plasma concentration after single dose administration. Individual plasma concentration-time data for WP1066 will be used to generate pharmacokinetic parameter estimates using both compartmental and non-compartmental methods.
Measure:Pharmacokinetic of WP1066: Area Under the Plasma Concentration-time Curve from time zero to 24 hours (AUC0-24)
Time Frame:Days 1, 2, 14, and 15 of course 1
Safety Issue:
Description:AUC0-24 is the area under the plasma concentration-time curve from time zero to 24 hours after the start of WP1066 and will be calculated using the linear trapezoidal. Individual plasma concentration-time data for WP1066 will be used to generate pharmacokinetic parameter estimates using both compartmental and non-compartmental methods.
Measure:Pharmacokinetic analysis of WP1066: Clearance from plasma (CL) following drug administration
Time Frame:Days 1, 2, 14, and 15 of course 1
Safety Issue:
Description:CL is the systemic (or total body) clearance from plasma following WP1066 administration. It will be determined by dose/AUC. Individual plasma concentration-time data for WP1066 will be used to generate pharmacokinetic parameter estimates using both compartmental and non-compartmental methods.
Measure:Pharmacokinetic analysis of WP1066: Elimination half life (t1/2)
Time Frame:Days 1, 2, 14, and 15 of course 1
Safety Issue:
Description:Elimination half-life (t1/2) will be calculated by 0.693/k. Individual plasma concentration-time data for WP1066 will be used to generate pharmacokinetic parameter estimates using both compartmental and non-compartmental methods.
Measure:Pharmacokinetic analysis of WP1066: Apparent volume of distribution
Time Frame:Days 1, 2, 14, and 15 of course 1
Safety Issue:
Description:Apparent volume of distribution will be calculated by Cl/k. Individual plasma concentration-time data for WP1066 will be used to generate pharmacokinetic parameter estimates using both compartmental and non-compartmental methods.
Measure:Pharmacokinetic analysis of WP1066: change in accumulation ratio of WP1066
Time Frame:Day 1 of cycle 1 (each cycle is 28 days) and Day 7 of cycle 1
Safety Issue:
Description:Accumulation ratio of WP1066 will be calculated as the ratio of AUC0-24 on cycle 1 Day 1 vs Cycle 1 fourth dose. Individual plasma concentration-time data for WP1066 will be used to generate pharmacokinetic parameter estimates using both compartmental and non-compartmental methods.
Measure:Pharmacodynamic analysis of WP1066: level of activated Stat3
Time Frame:Hours 0, 4, 24 of Day 1 and Hours 0, 4, 24 of Day 7
Safety Issue:
Description:Activated Stat3 is a transcription factor which in humans is encoded by the STAT3 gene. It is a member of the STAT protein family. The level of activated Stat3 (phospho-Stat3) will be measured in the peripheral blood mononuclear cells (PBMCs), the type of immune cells present in the blood, and the immune cytokines in the serum of subjects pre and post administration of the investigational drug.
Measure:Change in overall response rate (ORR) of WP1066 treatment
Time Frame:Up to 2 months after the last study drug dose
Safety Issue:
Description:Change in overall response rate (ORR) of WP1066 treatment for this pediatric study population in those with radiographically measurable disease.
Measure:Change in Immunological response
Time Frame:Up to 2 months after the last study drug dose
Safety Issue:
Description:If clinically indicated and as an optional procedure, biopsy or surgery specimens of the tumors will be obtained to determine the molecular expression of p-STAT3, Ki-67 and immunological characteristics of the tumors (Treg infiltration, co-stimulator molecule expression, etc.)
Measure:Time to radiographically assessed progression and/or response to treatment with WP1066.
Time Frame:Up to 2 months post-intervention
Safety Issue:
Description:The subjects will undergo imaging at baseline and again within 30 days after obtaining the MRI that aroused the suspicion of progression, or an alternative imaging method can be employed, such as MRI with spectroscopy and/or perfusion, or positron emission tomography (PET).
Measure:Change in progression-free survival (PFS)
Time Frame:Up to 2 months after the last study drug dose
Safety Issue:
Description:The PFS will be defined radiographically as a greater than 25% increase in tumor volume (in malignant glioma) on T1-weighted MRI scans compared with the MRI obtained within 4 weeks before enrollment. Estimated using Kaplan-Meier survival curves. Cox proportional hazards regression methodology may be used to assess the association between duration of response or survival and clinical and demographic characteristics of interest.
Measure:Change in overall survival (OS)
Time Frame:Up to 2 months after the last study drug dose
Safety Issue:
Description:Estimated using Kaplan-Meier survival curves. Cox proportional hazards regression methodology may be used to assess the association between duration of response or survival and clinical and demographic characteristics of interest.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Emory University

Trial Keywords

  • Brain Tumor

Last Updated

April 15, 2020