Metarrestin (ML-246) In Subjects With Metastatic Solid Tumors

Study Overview

Metarrestin (ML-246) in Subjects With Metastatic Solid Tumors

Background: Metastasis is the spread of cancer from one organ to a nonadjacent organ. It causes 90% of cancer deaths. No treatment specifically prevents or reduces metastasis. Researchers hope a new drug can help. It stops cancer cells from growing and spreading further and possibly shrink cancer lesions in distant organs. Objective: To find a safe dose of metarrestin and to see if this dose shrinks tumors. Eligibility: Adults age 18 and older with pancreatic cancer, breast cancer, or a solid tumor that has not been cured by standard therapies. Also, children age 12-17 with a solid tumor (other than a muscle tumor) with no standard therapy options. Design: Participants will be screened with: * blood tests * physical exam * documentation of disease confirmation or tumor biopsy * electrocardiogram to evaluate the heart * review of their medicines and their ability to do their normal activities Participants will take metarrestin by mouth until they cannot tolerate it or stop to benefit from it. They will keep a medicine diary. Participants will visit the Clinical Center. During the first month there are two brief hospital stays required with visits weekly or every other week thereafter. They will repeat some of the screening tests. They will fill out questionnaires. They will have tests of their cognitive function. They will have an electroencephalogram to record brain activity. They will have a computed tomography (CT) scan or magnetic resonance imaging (MRI). A CT is a series of X-rays of the body. An MRI uses magnets and radio waves to take pictures of the body. Adult participants may have tumor biopsies. Participants will have a follow-up visit 30 days after treatment ends. Then they will have follow-up phone calls or emails every 6 months for the rest of their life or until the study ends. ...

Background: Metarrestin is a first-in-class investigational agent targeting the peri-nucleolar compartment (PNC), a marker of genome organization associated with metastasis. Preclinical studies have shown that metarrestin effectively suppresses metastasis and extends overall survival in different cancer models. Multi-species allometric scaling and good laboratory practice (GLP) toxicology and toxicokinetic studies indicate that metarrestin administered at a calculated safe maximum recommended starting dose (MRSD) to human subjects is predicted to afford intratumoral exposure levels within the therapeutic range observed preclinically. Objectives: Phase IA: To determine the maximum tolerated dose (MTD) of metarrestin. Phase IB: To determine the Objective Response Rate (ORR) according to Evaluation Criteria (RECIST 1.1) in patients treated with metarrestin at the MTD. Eligibility: Adult subjects with any advanced solid tumors (Cohort IA), or pancreatic, colorectal, or breast tumors (Cohort IB1). OR Pediatric subjects age 12 and older with solid tumors other than rhabdomyosarcoma (RMS) including embryonal, alveolar, spindle cell/sclerosing, and pleomorphic subtypes of RMS (Cohort IB2). Patients must have progressed on prior standard chemotherapeutic therapy. Design: This is first-in-human Phase I trial to investigate the safety and clinical activity of metarrestin in subjects with metastatic solid tumors. During Phase IA MTD of metarrestin will be estimated in adult patients with solid tumors. During Phase IB adult patients with breast, colorectal, or pancreatic cancer, and pediatric patients with solid organ cancer will be treated at dose level of estimated MTD. Patients will receive treatment in cycles consisting of 28 (+7/- 2) days. Metarrestin will be administered PO until progression or unacceptable toxicity.

Advanced Solid Tumors
Metastatic Pancreatic Cancer
Pediatric Solid Tumor
Advanced Breast Cancer
Malignant Peripheral Nerve Sheath Tumor
Colorectal Neoplasms

DRUG: Metarrestin

200023
20-C-0023

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2020-01-07	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2025-09-11
First Submitted that Met QC Criteria 2020-01-08	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ESTIMATED) 2025-09-12
First Posted (ESTIMATED) 2020-01-10	Results First Posted N/A	Last Verified 2025-09-10

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Sequential

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: 1/Arm 1 Escalating/de-escalation doses of metarrestin	DRUG: Metarrestin Phase IA: Loading dose on Day 1 of Cycle 1 for Dose Levels 1-7. Loading dose on Days 1 and 3 of Cycle 1 for Dose Levels 8-11. After the loading dose on Day 1 or Days 1 and 3 of Cycle 1, continue on Mondays-Wednesdays-Fridays of every following cycle. Phas
EXPERIMENTAL: 2/Arm 2 MTD of metarrestin	DRUG: Metarrestin Phase IA: Loading dose on Day 1 of Cycle 1 for Dose Levels 1-7. Loading dose on Days 1 and 3 of Cycle 1 for Dose Levels 8-11. After the loading dose on Day 1 or Days 1 and 3 of Cycle 1, continue on Mondays-Wednesdays-Fridays of every following cycle. Phas

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: 1/Arm 1

Escalating/de-escalation doses of metarrestin

DRUG: Metarrestin

Phase IA: Loading dose on Day 1 of Cycle 1 for Dose Levels 1-7. Loading dose on Days 1 and 3 of Cycle 1 for Dose Levels 8-11. After the loading dose on Day 1 or Days 1 and 3 of Cycle 1, continue on Mondays-Wednesdays-Fridays of every following cycle. Phas

EXPERIMENTAL: 2/Arm 2

MTD of metarrestin

DRUG: Metarrestin

Phase IA: Loading dose on Day 1 of Cycle 1 for Dose Levels 1-7. Loading dose on Days 1 and 3 of Cycle 1 for Dose Levels 8-11. After the loading dose on Day 1 or Days 1 and 3 of Cycle 1, continue on Mondays-Wednesdays-Fridays of every following cycle. Phas

Primary Outcome Measures	Measure Description	Time Frame
To identify the maximum tolerated dose (MTD) of metarrestin in subjects with metastatic solid tumors	MTD of metarrestin	28 days
To determine the Objective Response Rate (ORR) according to Evaluation Criteria (RECIST 1.1) in patients treated with metarrestin at the MTD	Fraction of objective responses determined and reported as the ORR	every 2 months

Secondary Outcome Measures	Measure Description	Time Frame
To determine the Objective Response Rate (ORR) according to Evaluation Criteria (RECIST 1.1) in patients treated with metarrestin at the MTD in Cohort IB1	The ORR rate will be determined by dividing the number of patients with an objective response by the number of evaluable patients who are treated at the MTD for cohort Phase IB1	every 2 months
To determine plasma PK levels of metarrestin in humans	The pharmacokinetic (PK) profile of metarrestin will be derived from single dose and multiple dose PK measures for each dose level collecting the standard pharmacokinetic parameters	28 days
To assess progression-free survival (PFS) according to RECIST 1.1	Median amount of time subject survives without disease progression after treatment	at progression
To determine duration of overall response (DOR) rate according to Response Evaluation Criteria (RECIST 1.1) in subjects with metastatic solid tumors	Kaplan-Meier curves beginning at the date of response will be used and will be determined in all responding patients treated on the Phase IB expansion cohorts	at progression
To determine tolerability of the adult recommended dose in children >= 12 year of age (Cohort IB2)	The fraction of patients who can tolerate the dose	28 days after treatment discontinuation
To assess safety and tolerability of metarrestin (Cohort IB1)	All treatment-related AEs will be captured, and for each grade, the number and type of AE per dose level will be descriptively described in Cohort 1B1	28 days after treatment discontinuation
To assess safety and tolerability of metarrestin in subjects with metastatic solid tumors	All treatment-related AEs will be captured, and for each grade, the number and type of AE per dose level will be descriptively described	28 days after treatment discontinuation

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Murielle Hogu

Phone Number: (240) 858-3335

Email: murielle.hogu@nih.gov

Study Contact Backup

Name: Udo Rudloff, M.D.

Phone Number: (240) 760-6238

Email: rudloffu@mail.nih.gov

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
12 Years

Accepts Healthy Volunteers:

INCLUSION CRITERIA:
Adult (>= 18 years) subjects with:

histologically or cytologically confirmed solid tumors (Phase IA).

Pediatric (>=12 and < 18 years) subjects with histologically or cytologically confirmed solid tumors other than rhabdomyosarcoma (RMS) including embryonal, alveolar, spindle cell/sclerosing and pleomorphic subtypes of RMS (Phase IB).
Subjects must have disease that:

is not amenable to potentially curative resection,
spread at least to one other organ system other than primary tumor or recurred after removal of primary tumor
has site measurable per RECIST 1.1
progressed on or after at least one line of standard systemic chemotherapy (Phase IA and IB1)
have no standard therapy option available (Phase IB2)
Patients must have recovered from any acute toxicity related to prior therapy or surgery or disease to a grade 1 or less.
Performance status

Adequate hematological function defined by:

absolute neutrophil count (ANC) >= 1.0 x 10(9)/L,
transfusion-independent platelet count >= 100 x 10(9)/L,
Hgb >= 9 g/ dL (patients who have received <= 2 PRBC transfusions within 48 hours are eligible)
Adequate coagulation as defined by:

Adequate hepatic function defined by:

a total bilirubin level <= 1.5 x ULN, (total bilirubin <= 2.0 x ULN in case of prior diagnosis of Gilbert syndrome)
an AST level <= 3xULN
an ALT level <= 3 xULN
Adequate renal function defined by:

Creatinine OR Measured or calculated creatinine clearance (CrCl) (eGFR may also be used in place of CrCl)

Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard.
The effects of the study treatment on the developing human fetus are unknown; thus, individuals of childbearing potential and individuals who can father children must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior

Nursing participants must be willing to discontinue nursing at the time of the study treatment initiation.
Weight >= 35 kg.
Ability of subject or parent/guardian to understand and the willingness to sign a written informed consent document.
Subjects must have lesion(s) accessible for biopsy (other than used for measurement of disease) and be willing to undergo mandatory study biopsies (Cohort IB1 only).
Ability to swallow oral capsules.

Anticancer treatment within designated period before treatment initiation including:

minor surgical procedure (such as biliary stenting) within 14 days. Note: if liver function tests after biliary stenting or renal function tests after ureteral stenting return to normal, within 5 days after biliary or ureteral stenting;
major surgical procedure or curative radiation treatment within 28 days;
palliative radiation treatment within 14 days;
chemotherapy or experimental drug treatment with published half-life known to be 72 hours or less within 14 days;
experimental drug treatment with unpublished or half-life greater than 72 hours within 28 days;
chemotherapy regimen containing an alkylating antineoplastic agent (cyclophosphamide, chlorambucil, melphalan, or ifosfamide), alkylating-like (platinumbased chemotherapeutic drugs, platinum analogues), and non-classical alkylating agent (dacarbazine, temozolomide) within 28 days.
Patients receiving any medications or substances that are moderate and strong inhibitors or inducers of CYP3A4 and are not able to safely stop these medications are excluded from this study; patients must stop strong CYP3A4 inhibiting/inducing medications within 5 published half-lives and moderate within 3 published half-lives prior to the treatment initiation.

Subjects with cardiomyopathy diagnosed within 6 months prior to treatment initiation including but not limited to the following:

hypertrophic cardiomyopathy
arrhythmogenic right ventricular cardiomyopathy
abnormal ejection fraction (echocardiogram [ECHO]) <= 53% (if a range is given then the upper value of the range will be used)
previous moderate or severe impairment of left ventricular systolic function (LVEF <45%)
severe valvular heart disease
atrial fibrillation with a ventricular rate >100 bpm on EKG at rest
Fridericia's corrected QT interval (QTcF) >= 480 msec (adults) or >= 460 msec (pediatric subjects, aged 12 to <18 years) or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome.
HIV, HCV, HBV positive patients on antiviral drugs are excluded due to the absence of previous experience with concurrent use of antiviral medications and the investigational drug product to be evaluated in the current study and possible for adverse pharmacokinetic and/or pharmacodynamic interactions.
Previous malignant disease (other than the target malignancy to be investigated in this trial) within the last 3 years. Note: subjects with a history of cervical carcinoma in situ, superficial or non-invasive bladder cancer, or basal cell or squamous cell carcinoma in situ previously treated with curative intent are NOT excluded.
Rapidly progressive disease which, in the opinion of the Investigator, may predispose to inability to tolerate treatment or trial procedures.
Subjects with central nervous system (CNS) metastases or CNS disorders known to increase possible neurotoxicity of metarrestin in case of compromised blood-brain barrier (e.g. recent stroke (<3 months of treatment initiation), infectious causes).
Significant acute or chronic infections including tuberculosis with presence of clinical symptoms or physical findings.
Patients with a history of any seizures or increased risk of seizures on screening EEGs defined by 1) interictal epileptiform discharges, 2) temporal intermittent rhythmic delta activity (TIRDA), or 3) electrographic or clinical seizures on EEG.
Clinically relevant diseases (for example, inflammatory bowel disease) and / or uncontrolled medical conditions, which, in the opinion of the Investigator, might impair the subject's tolerance or ability to participate in the trial.
Patients with previous gastric bypass, patients receiving nutrition via feeding tubes or parenterally, or patients with malabsorptive conditions (damage to the intestine from infection, inflammation, trauma, or surgery, celiac disease, Crohn's disease, chronic pancreatitis, or cystic fibrosis resulting malabsorption). Patients with refractory nausea and vomiting. Note: patients with gastric banding are allowed.
Pregnant individuals.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

PRINCIPAL_INVESTIGATOR: Udo Rudloff, M.D., National Cancer Institute (NCI)

Publications

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