Clinical Trials /

Ulixertinib (BVD-523) and Hydroxychloroquine in Patients w Advanced MAPK-Mutated Gastrointestinal Adenocarcinomas

NCT04145297

Description:

Open-label dose escalation of Ulixertinib combined with fixed dose of hydroxychloroquine.

Related Conditions:
  • Cholangiocarcinoma
  • Colorectal Carcinoma
  • Esophageal Carcinoma
  • Gastric Carcinoma
  • Pancreatic Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ulixertinib (BVD-523) and Hydroxychloroquine in Patients w Advanced MAPK-Mutated Gastrointestinal Adenocarcinomas
  • Official Title: A Phase I Trial of Ulixertinib (BVD-523) and Hydroxychloroquine in Patients With Advanced MAPK-Mutated Gastrointestinal Adenocarcinomas

Clinical Trial IDs

  • ORG STUDY ID: HCI127114
  • NCT ID: NCT04145297

Conditions

  • Gastrointestinal Neoplasms

Interventions

DrugSynonymsArms
UlixertinibBVD-523Treatment: all patients
HydroxychloroquineTreatment: all patients

Purpose

Open-label dose escalation of Ulixertinib combined with fixed dose of hydroxychloroquine.

Detailed Description

      This is an open-label Phase I basket trial designed to determine the phase 2 recommended dose
      of ulixertinib in combination hydroxychloroquine. The recommended phase 2 dose (RP2D) will be
      determined by using a standard 3+3 dose-escalation design with a minimum of 3 evaluable
      subjects accrued to dose level one and two. Should dose level one be deemed intolerable,
      enrollment will proceed at dose level 0. The RP2D will be affirmed according to the rules of
      the 3+3 dose-escalation scheme
    

Trial Arms

NameTypeDescriptionInterventions
Treatment: all patientsExperimentalHydroxychloroquine will be provided as 200 mg tablets and will be self-administered by mouth twice daily. Ulixertinib will be provided as 150 mg capsules and will be self-administered twice daily by mouth at the assigned dose level. Both medications will be administered in 28-day cycles
  • Ulixertinib
  • Hydroxychloroquine

Eligibility Criteria

        Inclusion Criteria:

          -  Male or female subject aged ≥ 18 years.

          -  Subject with histologically confirmed MAPK-mutated GI malignancies: KRAS, NRAS, HRAS,
             BRAFnon-V600, MEK, and ERK.

          -  Subject is willing to provide a baseline biopsy.

          -  Prior lines of therapy:

               -  For patients with cholangiocarcinoma: subject must have progressed during or
                  after one line of therapy.

               -  For patients with pancreatic adenocarcinoma: the subject must have progressed
                  during or after one line of therapy.

               -  For patients with colorectal carcinoma: the subject must have progressed during
                  or after two lines of therapy.

               -  For patients with stomach or esophageal carcinoma: the subject must have
                  progressed during or after two lines of therapy.

          -  Subject must have measurable disease by RECIST 1.1 criteria by CT or MRI.

          -  ECOG Performance Status ≤ 1.

          -  Adequate organ function as defined as:

               -  Hematologic:

                    -  Absolute neutrophil count (ANC) ≥ 1500/mm3

                    -  Platelet count ≥ 100,000/mm3

                    -  Hemoglobin ≥ 10 g/dL

               -  Hepatic:

                    -  Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)

                    -  AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN

                    -  Patients with liver metastases will be allowed to enroll with AST and ALT
                       levels ≤ 5 x ULN.

               -  Renal:

                    -  Estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula:

                    -  Males: ((140-age)×weight[kg])/(serum creatinine [mg/dL]×72)

                    -  Females: (((140-age)×weight[kg])/(serum creatinine [mg/dL]×72))×0.85

          -  Evidence of post-menopausal status or negative urinary or serum pregnancy test for
             female pre-menopausal patients. Women will be considered post-menopausal if they have
             been amenorrheic for 12 months without an alternative medical cause. The following
             age-specific requirements apply:

               -  Women < 50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone
                  levels in the post-menopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).

               -  Women ≥ 50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal
                  treatments, had radiation-induced menopause with last menses >1 year ago, had
                  chemotherapy-induced menopause with last menses >1 year ago, or underwent
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy).

          -  Highly effective contraception for both male and female subjects throughout the study
             and for at least 4 months after last study treatment administration (see Section 7.6).

          -  Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior
             treatments, unless AE(s) are clinically non-significant and/or stable on supportive
             therapy.

          -  Able to provide informed consent and willing to sign an approved consent form that
             conforms to federal and institutional guidelines.

        Exclusion Criteria:

          -  Subject has received systemic antineoplastic therapy (including unconjugated
             therapeutic antibodies and toxin immunoconjugates) or any investigational therapy ≤ 14
             days or within 5 half-lives prior to starting study treatment, whichever is shorter.

          -  Subject has received radiotherapy ≤ 14 days prior to the first dose of study
             treatment. Localized radiation therapy for the treatment of symptomatic bone
             metastasis is allowed during that timeframe.

          -  Subjects who have undergone major surgery ≤ 3 weeks prior to starting study drug or
             who have not fully recovered from major surgery.

          -  Presence of peritoneal carcinomatosis (PC).

          -  Diagnosis of any other malignancy within 2 years prior to study enrollment, except for
             adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the
             breast, bladder or of the cervix, and low-grade (Gleason 6 or below) prostate cancer
             on surveillance with no plans for treatment intervention (eg, surgery, radiation, or
             castration) or prostate cancer that has been adequately treated with prostatectomy or
             radiotherapy and currently with no evidence of disease or symptoms is allowed.

          -  Known brain metastases or cranial epidural disease.

             --Note: Brain metastases or cranial epidural disease adequately treated with
             radiotherapy and/or surgery and stable for at least 4 weeks before the first dose of
             study treatment will be allowed on trial. Subjects must be neurologically asymptomatic
             and without corticosteroid treatment at the time of first dose of study treatment.

          -  History or current evidence of retinal vein occlusion (RVO) or current risk factors
             for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
             or hypercoagulability syndromes).

          -  Current evidence of uncontrolled, significant intercurrent illness including, but not
             limited to, the following conditions:

               -  Cardiovascular disorders:

               -  Congestive heart failure New York Heart Association Class 3 or 4, unstable angina
                  pectoris, serious cardiac arrhythmias.

               -  Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI),
                  or other ischemic events, or thromboembolic event (eg, deep venous thrombosis,
                  pulmonary embolism) within 3 months before first dose.

               -  QTc prolongation defined as a QTcF > 500 ms.

               -  History of seizures

               -  Impairment of gastrointestinal function or gastrointestinal disease (e.g.,
                  ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption
                  syndrome, or small bowel resection under the judgment of the PI may impair
                  absorption of study drugs).

               -  Any other condition that would, in the Investigator's judgment, contraindicate
                  the patient's participation in the clinical study due to safety concerns or
                  compliance with clinical study procedures, e.g., infection/inflammation,
                  intestinal obstruction, unable to swallow medication.(patients may not receive
                  drug through a feeding tube), social/ psychological issues, etc.

          -  Known HIV infection with a detectable viral load within 6 months of the anticipated
             start of treatment.

             --Note: Patients on effective antiretroviral therapy with an undetectable viral load
             within 6 months of the anticipated start of treatment are eligible for this trial.

          -  Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination, radiographic findings, and TB testing in line with
             local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or
             hepatitis C.

             --Note: Patients with a past or resolved HBV infection (defined as the presence of
             hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients
             positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction
             is negative for HCV RNA.

          -  Medical, psychiatric, cognitive or other conditions that may compromise the patient's
             ability to understand the patient information, give informed consent, comply with the
             study protocol or complete the study.

          -  Known prior severe hypersensitivity to investigational product or any component in its
             formulations (NCI CTCAE v5.0 Grade ≥ 3).

          -  Subjects taking prohibited medications as described in Section 6.4. A washout period
             of prohibited medications for a period of at least 5 half-lives or as clinically
             indicated should occur prior to the start of treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose of ulixertinib in combination with a fixed dose of hydroxychloroquine in subjects with advanced, RAS, non-V600 BRAF, ERK or MEK mutated gastrointestinal malignancies
Time Frame:the day of the first dose, cycle one day one, to cycle one day 28 (Cycle=28 days)
Safety Issue:
Description:The incidence of DLTs during the defined DLT period

Secondary Outcome Measures

Measure:Safety and tolerability of ulixertinib and hydroxychloroquine in the study population: adverse events (AEs) and serious adverse events (SAEs)
Time Frame:Any patient who has taken at least one dose of both ulixertinib and hydroxychloroquine will be evaluable for toxicity. Assessment will be completed through safety follow-up visit at 60 days after the end of treatment visit.
Safety Issue:
Description:The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by type, severity (as defined by the NIH CTCAE, version 5.0), seriousness, duration, and relationship to study treatment
Measure:Efficacy of ulixertinib and hydroxychloroquine in the study population: Objective response rate (PR and CR)
Time Frame:Patients will be evaluable for response once they have completed the first cycle of treatment and completed the C2D1 CT Scan.Assessment will be completed through safety follow-up visit at 60 days after the end of treatment visit.
Safety Issue:
Description:Objective response rate (PR and CR) will be described

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Utah

Last Updated

April 6, 2020