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Oral AMXT 1501 Dicaprate in Combination With IV DFMO

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ClinicalTrials.gov Identifier: NCT05500508
Recruitment Status : Recruiting
First Posted : August 15, 2022
Last Update Posted : August 15, 2022
Sponsor:
Information provided by (Responsible Party):
Aminex Therapeutics, Inc.

Brief Summary:
A Phase 1B/2A study will be conducted to establish safety and dose level of AMXT 1501 dicaprate in combination with IV DFMO, in cancer patients.

Condition or disease Intervention/treatment Phase
Cancer Solid Tumor Solid Carcinoma Advanced Cancer DIPG Brain Tumor Ovary Cancer Breast Cancer Papillary Thyroid Cancer Head and Neck Cancer Gastric Cancer Nsclc Mesotheliomas Pleural Mesothelioma Peritoneum Esophageal Cancer Diffuse Midline Glioma, H3 K27M-Mutant Endometrial Cancer Cervical Cancer Melanoma Colorectal Cancer Drug: AMXT1501 Drug: DFMO Phase 1 Phase 2

Detailed Description:
The objective of this study is to determine the safety and tolerability of oral AMXT 1501 dicaprate (AMXT1501) in combination with IV DFMO in patients with advanced solid tumors, or DIPG/DMG. Secondary objectives include characterization of plasma pharmacokinetics (PK), pharmacodynamic (PD), and other biomarker efficacy assessments of the impact of AMXT 1501 in combination with IV DFMO on polyamine uptake by circulating lymphocytes (blood cells). To these aims, the study will evaluate the safety, PK, PD, and other biomarker efficacy profiles of orally-administered AMXT 1501 and IV DFMO. Approximately, 56 patients will be enrolled to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AMXT 1501 and IV DFMO in combination. The MTD is defined as the highest dose level below at which dose escalation is stopped.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1B/2A Study of the Safety, Tolerability and Initial Efficacy of Oral AMXT 1501 Dicaprate and Intravenous Difluoromethylornithine (DFMO) in Patients With Cancer
Actual Study Start Date : August 8, 2022
Estimated Primary Completion Date : October 30, 2023
Estimated Study Completion Date : December 31, 2023


Arm Intervention/treatment
Experimental: Escalation

Dose escalation of DFMO with AMXT1501 fixed dose will follow a 3 + 3 dose escalation design.

The AMXT 1501 starting dose administered in the first cohort will be 1200mg total daily dose (200 mg capsules; 3 capsules in morning; 3 capsules in evening) along with IV DFMO administered in continuous infusion at 2mL/hr over a 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 cohort.

Drug: AMXT1501
AMXT 1501 dicaprate is D-lys(palmitoyl)-spermine dicaprate salt in 200 mg (free base content) enterically-coated capsules

Drug: DFMO
DFMO is DL-2-(difluoromethyl) ornithine monohydrochloride monohydrate provided as a 200 mg/mL aqueous solution in 20 mL vials.
Other Name: difluoromethyl ornithine monohydrochloride

Experimental: Expansion
The expansion cohort will include up to 40 evaluable patients at a proposed RP2D level of AMXT1501 and DFMO defined by AMXT1501-101A study to further characterize safety at proposed RP2D dose level with repeat dosing, and characterize early anti-tumor activity.
Drug: AMXT1501
AMXT 1501 dicaprate is D-lys(palmitoyl)-spermine dicaprate salt in 200 mg (free base content) enterically-coated capsules

Drug: DFMO
DFMO is DL-2-(difluoromethyl) ornithine monohydrochloride monohydrate provided as a 200 mg/mL aqueous solution in 20 mL vials.
Other Name: difluoromethyl ornithine monohydrochloride




Primary Outcome Measures :
  1. Determine DLTs and RP2Ds in AMXT 1501 in combination with IV DFMO [ Time Frame: 1 year ]
    Indicate Number of patients with DLTs in AMXT1501 in combination with IV DFMO in patients with advanced cancer to determine the RP2D within the duration of the dose escalation period of the study as defined by the DLT definition of the protocol from baseline to end of Cycle 1

  2. Determine safety and tolerability of AMXT1501 in combination with IV DFMO [ Time Frame: 1 year ]
    To evaluate the safety and tolerability of AMXT1501 and IV DFMO combination in patients through collecting the number of patients with Treatment Related Adverse Events that occur in patients from first dose, AEs assessed by CTCAEv5.0


Secondary Outcome Measures :
  1. Determine the PK using AUC of AMXT 1501 and IV DFMO [ Time Frame: 6 months ]
    To evaluate the pharmacokinetics (PK) of AMXT 1501 in combination with IV DFMO in patients

  2. Determine the PK using Cmax of AMXT 1501 and IV DFMO [ Time Frame: 6 months ]
    To evaluate the pharmacokinetics (PK) of AMXT 1501 and IV DFMO

  3. Characterize investigator defined response Overall Response Rate (ORR) using RECIST v1.1 [ Time Frame: 6 months ]
    To characterize Investigator defined Overall Response Rate (ORR) using RECIST v1.1 response criteria.

  4. Characterize investigator defined Duration of Response (DOR) [ Time Frame: 6 months ]
    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.

  5. Characterize AMXT1501 and IV DFMO on the expression of immune related gene signatures [ Time Frame: 1 year ]
    Evaluate the effects of AMXT1501 and IV DFMO on the expression of immune related gene signatures, immune cell phenotype by IHC, AMXT1501 and DFMO drug levels impact on polyamine levels


Other Outcome Measures:
  1. Evaluate AMXT1501 and DFMO on PD biomarker by evaluating the level/concentration of polyamine uptake. [ Time Frame: 6 months ]
    Will evaluate the effect of AMXT1501 and DFMO on pharmacodynamic (PD) biomarker of polyamine uptake in the blood starting at Cycle 1 through the end of Cycle 2 and again at the beginning of each new cycle.



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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

4.2. Inclusion Criteria Patients will be eligible for study participation only if they meet ALL the inclusion criteria applicable to their diagnosis.

4.2.1. Patients Diagnosed with Advanced Solid Tumor(s)

  1. Understand and sign written IRB-approved informed consent form and be willing to comply with all study procedures. Refer to Section 9.4 for additional information on informed consent.
  2. Diagnosed with unresectable, locally advanced, or metastatic solid tumor for which no standard therapy is recognized or for which standard therapy has failed. Planned tumor types for evaluation include:

    • Platinum resistant* ovarian cancer (including - primary peritoneal cancer and fallopian tube cancer)

    • Breast cancer
    • Papillary thyroid cancer
    • Head and neck cancer
    • Gastric cancer
    • Non-small cell lung cancer (NSCLC)
    • Mesothelioma: Pleural and peritoneal
    • Esophageal
    • Endometrial cancer
    • Cervical
    • Melanoma
    • Colorectal cancers (colon, rectal)

      • Platinum-resistant is defined as disease that may have responded to a platinum-containing chemotherapy regimen, but there is documentation of demonstrated recurrence within 6 months following the completion of that platinum-containing regimen. Progressive disease of epithelial ovarian cancer (EOC) following platinum-based therapy can be documented by physical examination, computed tomography (CT) scans, or a doubling of cancer antigen 125 (CA-125) levels from either 1) upper limit of normal (ULN) or 2) most recent nadir value (per the Rustin criteria [Rustin et al., 2011]). For CA-125 to be used as a criterion for progressive disease, the CA-125 level nadir must have been above the ULN. In addition, the CA-125 nadir level must have been confirmed by a second measurement at least 1 week after the initial measurement.
  3. Must be >18 years of age.
  4. Histologically or cytologically documented disease.
  5. Has evaluable or measurable disease by RECIST v1.1 or mRECIST criteria.
  6. Provide tumor tissue from biopsy taken during Screening period.
  7. Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale.

    4.2.2. Patients Diagnosed with Diffuse Intrinsic Pontine Glioma or Diffuse Midline Glioma (Must also meet other generally noted criteria as noted within the protocol.

  8. For patients <18 years of age, the parents or legal guardians must understand and sign the written IRB-approved informed consent form (ICF). The patient, if able, must understand and sign the IRB-approved consent (assent) and be willing to comply with all study procedures.

    For patients ≥18 years of age, the patient must understand and sign written IRB-approved ICF and be willing to comply with all study procedures.

    Refer to Section 9.4 for additional information on informed consent.

  9. Diagnosed with DIPG or DMG.

    a. Any anatomic site of origin is acceptable.

  10. Must be ≥12 years of age and >40 kg in body weight.
  11. Radiologically documented disease.

    a. Patient with refractory or progressive DIPG or DMG, defined as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons, are eligible without histologic confirmation.

    b. Patients with brainstem tumors that do not meet radiographic criteria or are not considered to be typical DIPG or DMG will be eligible if the tumors have been biopsied and proven to be high-grade gliomas (such as anaplastic astrocytoma, glioblastoma, H3 K27M-mutant DMG).

  12. Has evaluable or measurable disease by RANO or RAPNO criteria.
  13. Provide cerebrospinal fluid (CSF) sample. Patients with pontine lesions for whom a radiological diagnosis of DIPG, DMG or high-grade gliomas is made will be eligible without a CSF sample, although CSF sample is strongly encouraged.
  14. Performance score:

    a. Patients >16 years of age, Karnofsky score ≥50%. b. Patients ≥12 and ≤16 years of age, Lansky ≥50%. Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

  15. Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy:

    1. Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea).
    2. Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta) or 7 days for short-acting growth factor.
    3. Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
    4. Immunotherapy: At least 42 days after the completion of any type of vaccination.
    5. Monoclonal antibodies: >21 days must have elapsed from the infusion of last dose of antibody and toxicity related to antibody therapy must be recovered to Grade ≤1.
    6. Radiation therapy: Patients must have had their last fraction of craniospinal or focal irradiation a minimum of 8-12 weeks prior to enrollment.
    7. Stem cell transplant: Patients must be ≥3 months since autologous stem cell transplant. Patients who received allogenic stem cell transplant or solid organ transplant are not eligible for study.

    4.2.3. All Patients - All patients are required to meet these inclusion exclusion criteria to be considered eligible for the study:

  16. Patient is able to take oral medications and willing to use an at-home infusion pump.
  17. Must have adequate bone marrow and renal/hepatic function at the screening and baseline visits, defined as:

    a. Absolute neutrophil count (ANC) ≥1.5×109/L without granulocyte colony-stimulating factor (G-CSF) support within 7 days preceding the lab assessment.

    b. Platelet ≥100×109/L, without transfusion within 7 days preceding the lab assessment.

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

    d. Activated partial thromboplastin time/ partial thromboplastin time (aPTT/PTT) ≤1.5×ULN.

    e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN (if liver metastases are present, then ≤5×ULN is allowed).

    f. Total serum bilirubin ≤1.5×ULN, (except for patients with known Gilbert's Syndrome in whom ≤3×ULN is permitted).

    Confirmation of Gilbert's diagnosis requires elevated unconjugated (indirect) bilirubin values; normal complete blood count in previous 12 months, blood smear, and reticulocyte count; normal aminotransferases and alkaline phosphatase in previous 12 months.

    g. The patient is clinically euthyroid. h. Renal: Serum creatinine <1.5×ULN or creatinine clearance ≥60 mL/min/1.73 m2 for patients with serum creatinine levels >1.5×ULN.

    i. 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).

  18. Active secondary malignancies will not be allowed, with the exception of:

    1. Adequately treated basal cell carcinoma, SCC of the skin, or in situ cervical cancer;
    2. Adequately treated Stage 1 cancer from which the subject is currently in remission and has been in remission for ≥2 years;
    3. Low-risk prostate cancer with Gleason score <7 and prostate-specific antigen <10 ng/mL, or
    4. Any other cancer from which the patient has been disease-free for ≥3 years.
  19. Patient compliance and geographic proximity (as determined by the Principal Investigator [PI]) to allow adequate follow-up.
  20. Both male and female patients must be willing to consent to using highly effective contraception (refer to Section 5.7) prior to study entry, while on treatment, and at least 3 months thereafter.

4.3. Exclusion Criteria Patients will not be eligible for study participation if they meet ANY of the exclusion criteria.

4.3.1. Patients Diagnosed with Advanced Solid Tumor(s)

  1. Have a seizure disorder where >1 seizure has occurred within the last year.
  2. Patient with treated (surgically excised or irradiated) with stable brain metastases are eligible as long as the treatment was at least 4 weeks prior to initiation of study drug and baseline brain CT with contrast or magnetic resonance imaging (MRI) within 2 weeks of initiation of study drug is negative for new brain metastases. Patients with stable brain metastases must not require therapy with corticosteroids.
  3. Treatment with radiation therapy, surgery, chemotherapy, or immunotherapy within 4 weeks prior to study entry (6 weeks for nitrosoureas or Mitomycin C). Limited prior palliative radiation may be permissible no less than 2 weeks prior to C1D1 with approval from the Medical Monitor.

    4.3.2. Patients Diagnosed with Diffuse Intrinsic Pontine Glioma or Diffuse Midline Glioma

  4. Patients with seizure disorders may be enrolled if seizures are well-controlled, defined as no increase in seizure frequency in the prior 7 days.

    1. Anticonvulsants should be used as clinically indicated.
    2. The use of enzyme inducing anticonvulsants is not permitted.
  5. Patient with treated (surgically excised or irradiated) with stable brain metastases are eligible as long as the treatment was at least 8 to 12 weeks prior to initiation of study drug and baseline brain CT with contrast or MRI within 2 weeks of initiation of study drug is negative for new brain metastases. Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible.

4.3.3. All Patients 6. Have 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, or history of cerebrovascular accident [CVA]) within 6 months of enrollment.

7. History or presence of an abnormal ECG that, in the Investigator's opinion, is clinically meaningful.

  1. Screening QTcF interval >480 ms is excluded. In the event that a single QTcF is >480 ms, the patient may enroll if the average QTcF for the 3 ECGs is <480 ms.
  2. For patients with an intraventricular conduction delay (QRS interval >120 ms), 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.
  3. 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. 8. Had major surgery, other than diagnostic surgery, within 4-weeks prior to Day 1.

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

    10. Women who are pregnant or lactating. NOTE: Women of childbearing potential (WOCBP) must have a "negative" serum pregnancy test within 1 week prior to treatment.

a. Women not OCBP is defined as: i. Postmenopausal with >1 year since last menses and:

  1. If <65 years old, follicle-stimulating hormone (FSH) >40 mIU/mL.
  2. If ≥65 years old and not on hormone replacement therapy (HRT), FSH >30 mIU/mL.
  3. If ≥65 years old and on HRT, the FSH requirement in not applicable. Postmenopausal females on HRT will be allowed if HRT has been stable for ≥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 ≥6 months prior to dosing study drug(s).

Note: Tubal ligation is not considered a form of permanent sterilization. 11. Patients may 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.). Patients who have an ongoing requirement for thyroid replacement therapy from prior exposure to a checkpoint inhibitor but who are clinically euthyroid are permitted.

12. Have an unwillingness or inability to comply with procedures required in this protocol.

13. Current active liver disease from any cause, including hepatitis A (hepatitis A virus immunoglobulin M positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Patients with HCV with undetectable virus after treatment are eligible. Patients with a prior history of HBV are eligible if quantitative polymerase chain reaction (PCR) for HBV DNA is negative. Note that elevated levels of biotin may interfere with viral serology testing.

14. Have a serious nonmalignant disease that, in the opinion of the Investigator or the Medical Monitor, could compromise protocol objectives.

15. Patients who are currently receiving any other investigational agent or who have received an investigational agent within the last 28 days, with the exception of any patient who participated in Study AMXT1501-101A.

16. Known GI 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.

17. Patients who have exhibited allergic reactions to a similar structural compound, biological agent, or formulation.

18. Use of luteinizing hormone-releasing hormone (LHRH) agonist / antagonists are not permitted.

19. Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 µg (NIH-ODS 2020; Section 5.9.2.1).

Note: Patients who switch from a high dose to a dose of ≤30 µg/day are eligible for study entry.

20. Infection with human immunodeficiency virus (HIV)-1 or HIV-2. Exception: Patients with well-controlled HIV (e.g., CD4 >350/mm3 and undetectable viral load) are eligible.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05500508


Contacts
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Contact: Project Manager 1-919-972-7312 daniel.ferrone@iqvia.com

Locations
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United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Rabia Khan    713-563-4667    rkhan@mdanderson.org   
Principal Investigator: Sarina Piha-Paul, MD         
Sponsors and Collaborators
Aminex Therapeutics, Inc.
Investigators
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Study Director: Nicole Gallegos, BS, MBA Aminex Therapeutics, Inc.
Study Chair: Jackie Walling, MBChB PhD Aminex Therapeutics, Inc.
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Responsible Party: Aminex Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT05500508    
Other Study ID Numbers: AMXT1501-102
First Posted: August 15, 2022    Key Record Dates
Last Update Posted: August 15, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Aminex Therapeutics, Inc.:
DFMO IV
AMXT 1501
DFMO
Additional relevant MeSH terms:
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Endometrial Neoplasms
Mesothelioma
Mesothelioma, Malignant
Thyroid Cancer, Papillary
Ovarian Neoplasms
Diffuse Intrinsic Pontine Glioma
Neoplasms
Neoplasms by Site
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Head and Neck Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Uterine Diseases
Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Thyroid Neoplasms
Endocrine Gland Neoplasms
Endocrine System Diseases
Thyroid Diseases
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms, Mesothelial