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

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ClinicalTrials.gov Identifier: NCT04222413
Recruitment Status : Not yet recruiting
First Posted : January 10, 2020
Last Update Posted : February 24, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief 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.


Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Metastatic Pancreatic Cancer Pediatric Solid Tumor Advanced Breast Cancer Malignant Peripheral Nerve Sheath Tumor Drug: Metarrestin Phase 1

Detailed 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).

OR

  • 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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.
Estimated Study Start Date : February 27, 2020
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2023


Arm Intervention/treatment
Experimental: 1/Arm 1
Escalating/de-escalation doses of metarrestin
Drug: Metarrestin
Phase IA: 1,2,4 or 6 mg PO every 48, 72 or 96 hours. Phase IB: PO according to the dose and schedule estimated during Phase IA

Experimental: 2/Arm 2
MTD of metarrestin
Drug: Metarrestin
Phase IA: 1,2,4 or 6 mg PO every 48, 72 or 96 hours. Phase IB: PO according to the dose and schedule estimated during Phase IA




Primary Outcome Measures :
  1. To identify the maximum tolerated dose (MTD) of metarrestin in subjects with metastatic solid tumors [ Time Frame: 28 days ]
    MTD of metarrestin

  2. To determine the Objective Response Rate (ORR) according to Evaluation Criteria (RECIST 1.1) in patients treated with metarrestin at the MTD [ Time Frame: every 2 months ]
    Fraction of objective responses determined and reported as the ORR


Secondary Outcome Measures :
  1. To assess safety and tolerability of metarrestin in subjects with metastaic solid tumors [ Time Frame: 28 days after treatment discontinuation ]
    All treatment-related AEs will be captured, and for each grade, the number and type of AE per dose level will be descriptively described

  2. To determine plasma PK levels of metarrestin in humans [ Time Frame: 28 days ]
    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

  3. 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 [ Time Frame: every 2 months ]
    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

  4. To determine the Objective Response Rate (ORR) according to Evaluation Criteria (RECIST 1.1) of metastatic versus primary lesions in patients treated with metarrestin at the MTD in Cohort IB1 [ Time Frame: every 2 months ]
    The ORR according to Evaluation Criteria (RECIST 1.1) in patients treated with metarrestin at the MTD (Cohort IB1 only) in metastatic versus primary lesions

  5. To assess safety and tolerability of metarrestin (Cohort IB1) [ Time Frame: 28 days after treatment discontinuation ]
    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

  6. To determine tolerability of the adult recommended dose in children = 12 year of age (Cohort IB2) [ Time Frame: 28 days after treatment discontinuation ]
    The fraction of patients who can tolerate the dose

  7. To determine duration of overall response (DOR) rate according to Response Evaluation Criteria (RECIST 1.1) in subjects with metastatic solid tumors [ Time Frame: at progression ]
    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

  8. To assess progression-free survival (PFS) according to RECIST 1.1 [ Time Frame: at progression ]
    Median amount of time subject survives without disease progression after treatment



Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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. See Section 6.3 for the evaluation of measurable disease,
    • 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) 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 < 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 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 IA 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 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 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.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04222413


Contacts
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Contact: Corrine M. Keen, R.N. (240) 760-6097 ckeen@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Udo Rudloff, M.D. National Cancer Institute (NCI)

Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04222413    
Other Study ID Numbers: 200023
20-C-0023
First Posted: January 10, 2020    Key Record Dates
Last Update Posted: February 24, 2020
Last Verified: January 13, 2020

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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 National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
First-In-Class Investigational Agent
Peri-Nuclear Compartment (PNC)
Effective Therpaies Against Metastasis
Oral Administration
Maximum Recommended Starting Dose
Additional relevant MeSH terms:
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Nerve Sheath Neoplasms
Neurofibrosarcoma
Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Fibrosarcoma
Neoplasms, Fibrous Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Sarcoma
Neurofibroma