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

STATUS

Recruiting
participants needed

54
sponsor

National Cancer Institute (NCI)

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Updated on 19 February 2024

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cancer

blood transfusion

breast cancer

platelet count

ct scan

renal function

metastasis

gilbert's syndrome

neutrophil count

solid tumor

MRI

x-rays

primary tumor

systemic chemotherapy

blood tests

electrocardiogram

blood test

electroencephalogram

renal function test

metarrestin

pediatric

pancreatic cancer

inherited long qt syndrome

muscle tumor

Summary

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.

Description

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 or breast tumors (Cohort IB1).

Pediatric subjects age 12 and older with solid tumors other than rhabdomyosarcoma and related skeletal muscle tumors (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 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 (+/- 3) days.
Metarrestin will be administered PO until progression or unacceptable toxicity.

Details

Condition	Nerve Sheath Tumors, Advanced Solid Tumors, Metastatic Pancreatic Cancer, Pediatric Solid Tumor, Advanced Breast Cancer
Age	12years - 100years
Treatment	Metarrestin
Clinical Study Identifier	NCT04222413
Sponsor	National Cancer Institute (NCI)
Last Modified on	19 February 2024

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	Adult (greater than or equal to 18 years) subjects with
	histologically or cytologically confirmed solid tumors (Phase IA)
	OR
	\--histologically or cytologically confirmed pancreatic or breast cancer
	(Phase IB)
	OR
	Pediatric (greater than or equal to 12 and < 18 years) subjects with histologically or cytologically confirmed solid tumors other than rhabdomyosarcoma or related skeletal muscle tumors (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
	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
	\--Karnofsky greater than or equal to 70% (for patients greater than or equal
	to16 years old), Lansky greater than or equal 70% (for patients <16 years old)
	Adequate hematological function defined by
	absolute neutrophil count (ANC) greater than or equal to 1.0 (SqrRoot) 10(9)/L
	transfusion-independent platelet count greater than or equal to 100 (SqrRoot) 10(9)/L
	Hgb greater than or equal to 9 g/ dL (patients who have received less than or equal to 2 PRBC transfusions within 48 hours are eligible)
	Adequate coagulation as defined by
	\--INR<1.5
	Adequate hepatic function defined by
	a total bilirubin level less than or equal to 1.5 (SqrRoot) ULN, (total bilirubin less than or equal to 2.0 x ULN in case of prior diagnosis of Gilbert syndrome)
	an AST level less than or equal to 3(SqrRoot) ULN
	an ALT level less than or equal to 3 (SqrRoot) ULN
	Adequate renal function defined by
	Creatinine OR Measured or calculated creatinine clearance (CrCl) (eGFR may also be used in place of CrCl)
	less than 1.5x institution upper limit of normal OR
	greater than 45 mL/min/1.73 m2 for participant with creatinine levels > 1.5 X institutional ULN
	Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard
	Subjects are required to have a QT interval of less than or equal to 460 ms (male) and less than or equal to 470 ms (female)
	Note: patients with known congenital QTc prolongation (inherited long QT
	syndrome (LQTS) due to e.g. Romano-Ward syndrome or others) are excluded
	The effects of the study treatment on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and up to 120 days after the last dose of the study drug(s). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
	Weight > 35 kg
	Ability of subject or Legally Authorized Representative 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
Exclusion Criteria
	Anticancer treatment within designated period before enrollment including
	minor surgical procedure (such as biliary stenting) within 14 days
	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 enrollment
	Note: dihydropyridinecalcium - channel blockers are permitted for management
	of underling disease
	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 due to unknown increase in neurotoxicity of metarrestin in case of compromised blood-brain barrier
	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 women are excluded from this study because metarrestin potential for teratogenic or abortifacient effects is unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with metarrestin, breastfeeding should be discontinued if the mother is treated with study drug

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