First-in-Human Phase I Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological and Clinical Activity of 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.
⁃ Adult (\>= 18 years) subjects with:
∙ histologically or cytologically confirmed solid tumors (Phase IA).
⁃ OR
• -histologically or cytologically confirmed pancreatic, colorectal, or breast cancer (Phase IB)
⁃ OR
⁃ 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
‣ -Karnofsky \>= 70% (for patients \>= 16 years old), Lansky \>= 70% (for patients \<16 years old)
⁃ 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:
‣ -INR\<1.5 (or \< 3.0 if subjects are currently taking anticoagulated medications) Note: increase of the upper limit of INR is restricted only to subjects who are receiving anticoagulation for medical reasons (DVT/PE prophylaxis, treatment for a thromboembolic event) and have increased INR because of these medications. Patients who have an elevated INR due to compromised liver function or any other medical conditions remain excluded
⁃ 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)
• --\< 1.5x institution upper limit of normal OR
• --\>= 45 mL/min/1.73 m\^2 for participant with creatinine levels \>= 1.5 X institutional ULN
‣ 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
⁃ to study entry, for the duration of study therapy and up to 120 days after the last dose of the study drug.
⁃ 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.