Clinical Trials /

Oral AMXT 1501 Dicaprate in Combination With DFMO

NCT03536728

Description:

A Phase 1 study will be conducted to establish safety and dose level of AMXT 1501 dicaprate alone, and in combination with DFMO, in cancer patients.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Oral AMXT 1501 Dicaprate in Combination With DFMO
  • Official Title: Phase I Dose-Finding, Safety Study of Oral AMXT 1501 Dicaprate and Difluoromethylornithine (DFMO) in Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: AMXT1501-101A
  • NCT ID: NCT03536728

Conditions

  • Cancer
  • Solid Tumor
  • Solid Carcinoma
  • Advanced Cancer

Interventions

DrugSynonymsArms
AMXT1501Part 1
DFMOdifluoromethyl ornithine monohydrochloridePart 1

Purpose

A Phase 1 study will be conducted to establish safety and dose level of AMXT 1501 dicaprate alone, and in combination with DFMO, in cancer patients.

Detailed Description

      The objective of this study is to determine the safety and tolerability of oral AMXT 1501
      dicaprate (AMXT1501) in combination with DFMO in patients with advanced solid tumors.
      Secondary objectives include characterization of plasma pharmacokinetics (PK) of AMXT 1501 as
      well as pharmacodynamic (PD) assessment of the impact of AMXT 1501 in combination with DFMO
      on polyamine uptake by circulating lymphocytes (blood cells).

      To these aims, the study will evaluate the safety, PK and PD profiles of orally-administered
      AMXT 1501 and DFMO. Approximately, 52 patients will be enrolled to determine the maximum
      tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AMXT 1501 and DFMO in
      combination. The MTD is defined as the highest dose level below at which dose escalation is
      stopped.
    

Trial Arms

NameTypeDescriptionInterventions
Part 1ExperimentalDose escalation of AMXT1501 with a fixed low dose of DFMO will follow a 3 + 3 dose escalation design. The AMXT 1501 starting dose administered in the first cohort will be 80 mg (2 capsules); each capsule contains 40 mg of active drug. The dose will be given orally, once daily, fasted state alone for 14 days, and starting on Day 15 AMXT 1501 80 mg given in combination with fixed low-dose oral DFMO at 250mg 2x per day (BID), for an additional 14 days; for a total 28 days of treatment per cycle. Cycle 2 includes AMXT1501 + DFMO that will be administered for 28 days. The patient can be treated for additional 28 day treatment cycles as deemed appropriate by their study investigator. Dose escalation of AMXT1501 alone will increase per Part 1 cohort.
  • AMXT1501
  • DFMO
Part 2ExperimentalDose escalation of DFMO with the Part 1 AMXT1501 RP2D fixed dose will follow a 3 + 3 dose escalation design. The AMXT 1501 starting dose administered in the first cohort will be one level below the AMXT 1501 Part 1 RP2D with 500 mg DFMO BID. The morning dose will be given orally of both AMXT1501 and DFMO, in a fasted state. The evening dose of DFMO alone will be given prior to bed-time for 28 days per cycle. The patient can be treated for additional 28 day treatment cycles as deemed appropriate by their study investigator. Dose escalation of DFMO alone will increase per Part 2 cohort.
  • AMXT1501
  • DFMO
ExpansionExperimentalThe expansion cohort will include up to 14 evaluable patients at a proposed RP2D level of AMXT1501 and DFMO defined by Part 2 to further characterize safety at proposed RP2D dose level with repeat dosing, and characterize early anti-tumor activity.
  • AMXT1501
  • DFMO

Eligibility Criteria

        Inclusion Criteria:

          1. Understand and sign, written Institutional Review Board (IRB)-approved informed
             consent form, and be willing to comply with all study procedures

          2. Participants must be > 18 years of age

          3. Patient is able to take oral medications

          4. Histologically or cytologically documented disease

          5. Unresectable, locally advanced or metastatic solid tumor for which no standard therapy
             is recognized or for which standard therapy has failed

          6. Has evaluable or measurable disease by RECIST v1.1 criteria

          7. Provide tumor tissue and/or archival tissue from original diagnostic block, if
             available for biomarker analysis

          8. Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale

          9. Normal auditory acuity: defined as a normal age-related audiogram without significant
             hearing loss.

         10. Must have adequate bone marrow and renal/hepatic function at the screening and
             baseline visits, defined as:

               1. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L without granulocyte
                  colony-stimulating factor (G-CSF) support within 7 days preceding the lab
                  assessment.

               2. Platelet ≥100 x 10^9/L, without transfusion within 7 days preceding the lab
                  assessment

               3. Hemoglobin ≥9 g/dL, without transfusion support within 7 days preceding the lab
                  assessment.

               4. Activated partial thromboplastin time/ partial thromboplastin time (aPTT/PTT)
                  ≤1.5 x ULN

               5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)≤ 2.5 × upper
                  limit of normal (ULN) (if liver metastases are present, then≤5 x ULN is allowed)

               6. Total serum bilirubin≤1.5 x ULN, (except for patients with known Gilbert's
                  Syndrome≤3 x ULN is permitted)

               7. Thyroid function (T4, and T3) are within normal limits

               8. Renal: Serum creatinine < 1.5 x ULN or creatinine clearance ≥60 mL/min/1.73m2 for
                  patients with serum creatinine levels above 1.5 x ULN.

               9. Any Grade 3 or higher lab abnormalities should be discussed and approved by the
                  Medical Monitor prior to enrollment (even if not considered clinically
                  significant);

         11. Patient compliance and geographic proximity (as determined by the Principal
             Investigator) that allow adequate follow-up.

         12. Both male and female patients must be willing to consent to using highly effective
             contraception prior to study entry, while on treatment and at least 3 months
             thereafter.

        Exclusion Criteria:

          1. Have a seizure disorder where > 1 seizure has occurred within the last year.

          2. Patient has clinically significant cardiovascular disease (e.g., significant cardiac
             conduction abnormalities, uncontrolled hypertension, myocardial infarction, cardiac
             arrhythmia or unstable angina, New York Heart Association Grade 3 or greater
             congestive heart failure, serious cardiac arrhythmia requiring medication, Grade 2 or
             greater peripheral vascular disease, and history of cerebrovascular accident (CVA))
             within 6 months of enrollment.

          3. History or presence of an abnormal electrocardiogram (ECG) that, in the Investigator's
             opinion, is clinically meaningful. Screening QTcF interval >480 ms is excluded. In the
             event that a single QTcF is >480 ms, the subject may enroll if the average QTcF for
             the 3 ECGs is < 480ms. For patients with an intraventricular conduction delay (QRS
             interval >120ms), the JTc interval may be used in place of the QTcF with Sponsor
             approval. The JTc must be <340 ms if JTc is used in place of the QTcF. Patients with
             an intraventricular delay due to a left bundle branch block are excluded; Note: QTcF
             prolongation due to pacemaker may enroll if the JTc is normal.

          4. Patient with treated (surgically excised or irradiated) and stable brain metastases
             are eligible as long as the treatment was at least 4 weeks prior to initiation of
             study drug and baseline brain computed tomography (CT) with contrast or magnetic
             resonance imaging (MRI) within 2 weeks of initiation of study drug is negative for new
             brain metastases. Subjects with stable brain metastases must not require therapy with
             corticosteroids

          5. Have major surgery, other than diagnostic surgery, within 4-weeks prior to Day 1

          6. Have active, bacterial, viral, or fungal infections, requiring systemic therapy

          7. Women who are pregnant or lactating. NOTE: Women of childbearing potential (WOCBP)
             must have a "negative" serum pregnancy test within one week prior to treatment.

             a) Women not OCBP defined as any of the following: i) Postmenopausal with > 1 year
             since last menses and:

        (1) If younger than 65 years old, with a follicle-stimulating hormone (FSH) > 40 mIU/mL (2)
        If older than 65 years old and not on hormone replacement therapy (HRT), with a FSH > 30
        mIU/mL (3) If older than 65 years old and on HRT, the FSH requirement in not applicable.
        Postmenopausal females on HRT will be allowed if the treatment is stable for at least 6
        months prior to dosing of study drug(s) (4) Written medical documentation of being
        sterilized (e.g. hysterectomy, double oophorectomy, bilateral salpingectomy) with the
        procedure performed at least 6 months prior to dosing study drug(s). Note: Tubal ligation
        is not considered a form of permanent sterilization (5) Should a woman become pregnant or
        suspect she is pregnant while participating in this study, she should inform her treating
        physician immediately.

        8) Have undergone treatment with radiation therapy, surgery, chemotherapy, immunotherapy or
        investigational therapy within one month prior to study entry (6 weeks for nitrosoureas or
        Mitomycin C). Patients may also not have any unresolved toxicity > grade 1 from previous
        anticancer therapy, except for stable chronic toxicities that are not expected to resolve
        (i.e. peripheral neuropathy, alopecia etc.)

        9) Have an unwillingness or inability to comply with procedures required in this protocol

        10) Has jaundice or known current active liver disease from any cause, including hepatitis
        A (hepatitis A virus immunoglobulin M (IgM) positive), hepatitis B (hepatitis B virus
        surface antigen (HBsAg) positive), or hepatitis C (hepatitis C virus (HCV) antibody
        positive, confirmed by HCV ribonucleic acid)

        11) Have a serious nonmalignant disease that in the opinion of the Investigator and/ or the
        Medical Monitor, could compromise protocol objectives in the opinion of the investigator
        and/or the sponsor

        12) Patients who are currently receiving any other investigational agent or who have
        received an investigational agent within the last 28 days

        13) Known gastrointestinal disease or procedure that could interfere with the absorption of
        study drug, including inability to swallow whole capsules or conditions that may interfere
        with absorption The medical monitor should be contacted for any questions regarding this
        exclusion criterion

        14) Patients who have exhibited allergic reactions to a similar structural compound,
        biological agent, or formulation
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine DLTs and RP2Ds in AMXT 1501 in combination with DFMO
Time Frame:1 year
Safety Issue:
Description:To evaluate dose-limiting toxicities (DLTs) of AMXT 1501 in combination with DFMO, in patients with advanced cancer and to establish a recommended Phase 2 dose (RP2D)

Secondary Outcome Measures

Measure:Determine the PK using AUC of AMXT 1501 and in combination with DFMO
Time Frame:6 months
Safety Issue:
Description:To evaluate the pharmacokinetics (PK) of AMXT 1501 alone and in combination with DFMO
Measure:Determine the PK using Cmax of AMXT 1501 and in combination with DFMO
Time Frame:6 months
Safety Issue:
Description:To evaluate the pharmacokinetics (PK) of AMXT 1501 alone and in combination with DFMO
Measure:Characterize investigator defined response Overall Response Rate (ORR) using RECIST v1.1
Time Frame:6 months
Safety Issue:
Description:To characterize Investigator defined Overall Response Rate (ORR) using RECIST v1.1 response criteria.
Measure:Characterize investigator defined Duration of Response (DOR)
Time Frame:6 months
Safety Issue:
Description:To characterize Investigator defined Duration of Response (DOR), using RECIST v1.1 response criteria and length of time (in days) from last study drug administration to time patient has progressive disease.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Aminex Therapeutics, Inc.

Trial Keywords

  • DFMO
  • AMXT 1501

Last Updated

January 17, 2019