- 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.
- 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.
-Adult subjects with any advanced solid tumors (Cohort IA), or pancreatic or breast tumors
- 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.
- 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
- 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.
- INCLUSION CRITERIA:
- Adult (greater than or equal to 18 years) subjects with:
- histologically or cytologically confirmed solid tumors (Phase IA).
--histologically or cytologically confirmed pancreatic or breast cancer (Phase IB)
- 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. See Section 6.3 for the evaluation of
- progressed on or after 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)
- 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:
- 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
- Subjects are required to have a QT interval of < 460 ms (male) and < 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
- 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 IA only).
- Ability to swallow oral capsules.
- Anticancer treatment within designated period before enrollment including:
- minor surgical procedure (such as biliary stenting) within 14 days;
- major surgical procedure or radiation treatment within 28 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
- 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
- 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.
- 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.