Oral AMXT 1501 Dicaprate in Combination With DFMO

• Sponsor: Aminex Therapeutics, Inc.
• Information provided by (Responsible Party): Aminex Therapeutics, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cancer; Solid Tumor; Solid Carcinoma; Advanced Cancer	Drug: AMXT1501; Drug: DFMO	Phase 1

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	52 participants
Allocation:	Non-Randomized
Intervention Model:	Sequential Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase I Dose-Finding, Safety Study of Oral AMXT 1501 Dicaprate and Difluoromethylornithine (DFMO) in Patients With Advanced Solid Tumors
Actual Study Start Date :	June 12, 2018
Estimated Primary Completion Date :	December 2019
Estimated Study Completion Date :	October 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1; Dose 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.	Drug: AMXT1501; AMXT 1501 dicaprate is D-lys(palmitoyl)-spermine dicaprate salt in 40 mg or 200 mg (free base content) enterically-coated capsules; Drug: DFMO; DFMO is DL-2-(difluoromethyl) ornithine monohydrochloride monohydrate 250 mg in hard gelatin capsules; Other Name: difluoromethyl ornithine monohydrochloride
Experimental: Part 2; Dose 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.	Drug: AMXT1501; AMXT 1501 dicaprate is D-lys(palmitoyl)-spermine dicaprate salt in 40 mg or 200 mg (free base content) enterically-coated capsules; Drug: DFMO; DFMO is DL-2-(difluoromethyl) ornithine monohydrochloride monohydrate 250 mg in hard gelatin capsules; Other Name: difluoromethyl ornithine monohydrochloride
Experimental: Expansion; The 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.	Drug: AMXT1501; AMXT 1501 dicaprate is D-lys(palmitoyl)-spermine dicaprate salt in 40 mg or 200 mg (free base content) enterically-coated capsules; Drug: DFMO; DFMO is DL-2-(difluoromethyl) ornithine monohydrochloride monohydrate 250 mg in hard gelatin capsules; Other Name: difluoromethyl ornithine monohydrochloride

Outcome Measures

Primary Outcome Measures :

1. Determine DLTs and RP2Ds in AMXT 1501 in combination with DFMO [ Time Frame: 1 year ]
   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 :

1. Determine the PK using AUC of AMXT 1501 and in combination with DFMO [ Time Frame: 6 months ]
   To evaluate the pharmacokinetics (PK) of AMXT 1501 alone and in combination with DFMO
2. Determine the PK using Cmax of AMXT 1501 and in combination with DFMO [ Time Frame: 6 months ]
   To evaluate the pharmacokinetics (PK) of AMXT 1501 alone and in combination with 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.

Other Outcome Measures:

1. Evaluate AMXT1501 in combination with DFMO on PD biomarker by evaluating the level/concentration of polyamine uptake in the blood. [ Time Frame: 6 months ]
   To evaluate the effect AMXT1501 in combination therapy with DFMO on pharmacodynamic (PD) biomarker of polyamine uptake

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Contacts

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Contact: Project Manager	1-919-972-7312	lrhodes@novellaclinical.com

Locations

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United States, Texas
MD Anderson Cancer Center	Recruiting
Houston, Texas, United States, 77030
Contact: Mary Nowak 713-563-1055 mnowak@mdanderson.org
Principal Investigator: Sarina Piha-Paul, MD
Next Oncology	Recruiting
San Antonio, Texas, United States, 78240
Contact: Research Coordinator 210-595-5300 crosas@nextsat.com
Principal Investigator: Anthony Tolcher, MD
United States, Virginia
Virginia Cancer Center	Recruiting
Fairfax, Virginia, United States, 22031
Contact: Melissa Hackmaster 703-208-9280 melissa.hackmaster@usoncology.com

Sponsors and Collaborators

Aminex Therapeutics, Inc.

Investigators

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Study Director:	Paul Schechter, MD, PhD	Aminex

More Information

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Responsible Party:	Aminex Therapeutics, Inc.
ClinicalTrials.gov Identifier:	NCT03536728 History of Changes
Other Study ID Numbers:	AMXT1501-101A
First Posted:	May 25, 2018
Last Update Posted:	January 21, 2019
Last Verified:	January 2019
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; AMXT 1501

Additional relevant MeSH terms:

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Eflornithine; Antineoplastic Agents; Trypanocidal Agents; Antiprotozoal Agents; Antiparasitic Agents	Anti-Infective Agents; Ornithine Decarboxylase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action