Clinical Trials /

IACS-010759 in Advanced Cancers

NCT03291938

Description:

This phase I trial studies the side effects and best dose of oxidative phosphorylation inhibitor IACS-010759 (IACS-010759) in treating participants with lymphoma that has come back or does not respond to treatment or solid tumors that have spread to other places in the body or cannot be removed by surgery. IACS-010759 may stop the growth of cancer or tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Breast Carcinoma
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: IACS-010759 in Advanced Cancers
  • Official Title: A Phase 1 Study to Evaluate the Safety and Tolerability of IACS-010759 in Subjects With Advanced Solid Tumors and Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 2017-0023
  • SECONDARY ID: NCI-2018-01042
  • SECONDARY ID: 2017-0023
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03291938

Conditions

  • Malignant Neoplasm of Breast
  • Malignant Neoplasms of Bone and Articular Cartilage
  • Malignant Neoplasms of Digestive Organs
  • Malignant Neoplasms of Female Genital Organs
  • Malignant Neoplasms of Lip Oral Cavity and Pharynx
  • Malignant Neoplasms of Male Genital Organs
  • Malignant Neoplasms of Mesothelial and Soft Tissue
  • Malignant Neoplasms of Respiratory and Intrathoracic Organs
  • Malignant Neoplasms of Thyroid and Other Endocrine Glands
  • Malignant Neoplasms of Urinary Tract
  • Malignant Neoplasms Stated as Primary Lymphoid Haematopoietic

Interventions

DrugSynonymsArms
IACS-010759IACS-010759 - Dose Escalation Cohort

Purpose

This phase I trial studies the side effects and best dose of oxidative phosphorylation inhibitor IACS-010759 (IACS-010759) in treating participants with lymphoma that has come back or does not respond to treatment or solid tumors that have spread to other places in the body or cannot be removed by surgery. IACS-010759 may stop the growth of cancer or tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and tolerability of IACS-010759, the maximum tolerated dose (MTD)
      and recommended phase 2 dose (RP2D) in subjects with any advanced solid tumor and lymphoma.

      SECONDARY OBJECTIVES:

      I. To evaluate IACS-010759 pharmacokinetics and preliminary antitumor activity (including
      overall response rate and duration of response).

      EXPLORATORY OBJECTIVES:

      I. To evaluate pharmacodynamic and exploratory predictive biomarkers of activity of
      IACS-010759.

      OUTLINE: This is a dose-escalation study.

      INDUCTION PHASE: Participants receive oxidative phosphorylation inhibitor IACS-010759 orally
      (PO) once daily (QD) on days 1-7 of course 1 in the absence of disease progression or
      unacceptable toxicity.

      MAINTENANCE PHASE: Participants receive oxidative phosphorylation inhibitor IACS-010759 PO QD
      on days 8 and 15 of course 1 and then on days 1, 8, and 15 of subsequent courses. Courses
      repeat every 21 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, participants are followed up at 30 days and then every
      3-6 months for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
IACS-010759 - Dose Escalation CohortExperimentalIACS-010759 administered daily on Days 1-7 of Induction Phase in a 21-day schedule. In the first cycle, IACS-010759 administered daily. Beginning dose of IACS-010759 depends on when participant joins this study.
  • IACS-010759
Breast Cancer - TNBC Expansion CohortExperimentalTNBC Expansion Cohort: Subjects with advanced TNBC with no available effective conventional treatment options. IACS-010759 administered on Day 8 and Day 15 in cycle 1. Doses administered on Days 1, 8 and 15 for all subsequent cycles. Beginning dose of IACS-010759 is maximum tolerated dose from Dose Escalation Cohort.
  • IACS-010759
Pancreatic Cancer - PDAC Expansion CohortExperimentalPDAC Expansion Cohort: Participants with advanced PDAC with no available effective conventional treatment options. IACS-010759 administered on Day 8 and Day 15 in cycle 1. Doses administered on Days 1, 8 and 15 for all subsequent cycles. Beginning dose of IACS-010759 is maximum tolerated dose from Dose Escalation Cohort.
  • IACS-010759
Biopsy Expansion CohortExperimentalBiopsy Expansion Cohort - Participants with tumors that can be safely biopsied on several occasions. IACS-010759 administered on Day 8 and Day 15 in cycle 1. Doses administered on Days 1, 8 and 15 for all subsequent cycles. Beginning dose of IACS-010759 is maximum tolerated dose from Dose Escalation Cohort.
  • IACS-010759

Eligibility Criteria

        Inclusion Criteria:

          -  Non-pregnant.

          -  Subjects must have histologically confirmed malignancy that is metastatic or
             unresectable and for which there is no available therapy likely to convey clinical
             benefit.

          -  Subjects must have received at least one line of systemic therapy in the
             advanced/metastatic setting. Subjects with diseases without known effective options
             are also eligible. a) Subjects with relapsed and/or refractory lymphoma must have had
             at least 2 prior lines of systemic therapy and are not candidates for high dose
             therapy/autologous stem cell transplant.

          -  Subjects must have evaluable disease for the dose escalation, and measurable disease
             for the dose expansion.

          -  Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of
             0 to 1.

          -  Subjects must have a life expectancy >= 12 weeks.

          -  Absolute neutrophil count >= 1,500/mcL.

          -  Hemoglobin >= 9 g/dL.

          -  Platelets >= 100,000/mcL.

          -  Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN).

          -  Aspartate transaminase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine
             transaminase (ALT) serum glutamic pyruvic transaminase (SGPT) =< 2.5 x institutional
             ULN or =< 5 x institutional ULN in the presence of liver metastases.

          -  Creatinine clearance >= 45 mL/min/1.73 m^2 for subjects with creatinine levels above
             institutional normal.

          -  Women of childbearing potential (WOCBP) must agree to use an adequate method of
             contraception during the study and until 3 months after the last treatment. Males must
             be surgically or biologically sterile or agree to use an adequate method of
             contraception during the study until 3 months after the last treatment. Adequate
             methods of contraception include: total abstinence when this is in line with the
             preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar,
             ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable
             methods of contraception.

          -  Female sterilization (have had surgical bilateral oophorectomy with or without
             hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
             case of oophorectomy alone, only when the reproductive status of the woman has been
             confirmed by follow up hormone level assessment; male sterilization (at least 6 months
             prior to screening). For female subjects on the study, the vasectomized male partner
             should be the sole partner for that subject.

          -  Combination of any of the two following (a+b or a+c or b+c): a) use of oral, injected
             or implanted hormonal methods of contraception or other forms of hormonal
             contraception that have comparable efficacy (failure rate < 1%), for example hormone
             vaginal ring or transdermal hormone contraception; b) placement of an intrauterine
             device (IUD) or intrauterine system (IUS); c) barrier methods of contraception: condom
             or occlusive cap (diaphragm or cervical/vault caps) with spermicidal
             foam/gel/film/cream/ vaginal suppository. In case of use of oral contraception, women
             should have been stable on the same pill before taking study treatment.

          -  Oral contraceptives are allowed but should be used in conjunction with a barrier
             method of contraception due to unknown effect of drug-drug interaction. Women are
             considered post-menopausal and not of child bearing potential if they have had 12
             months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g.
             age appropriate, history of vasomotor symptoms) or have had surgical bilateral
             oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago.
             In the case of oophorectomy alone, only when the reproductive status of the woman has
             been confirmed by follow up hormone level assessment is she considered not of child
             bearing potential.

          -  Subjects must have disease that can be safely biopsied (for RP2D biopsy expansion
             cohort only), and agree to undergo a pretreatment and on-treatment biopsy.

          -  Subjects with brain metastases must have completed treatment, either surgery or
             radiation, 4 weeks or longer prior to screening. A brain magnetic resonance imaging
             (MRI) demonstrating there is no current evidence of progressive brain metastases is
             required in subjects with previous brain metastasis. Patients with breast tissue
             expanders may have brain computerized tomography (CT) for assessment.

          -  Subjects must not be on full dose oral anticoagulation such as warfarin. Low dose
             warfarin and prophylactic as well as therapeutic low molecular weight heparin are
             allowable.

          -  Subjects who enroll in the triple-negative breast cancer (TNBC) dose expansion cohort
             should adhere to the American Society for Clinical Pathology (ASCP)/College of
             American Pathologists (CAP) guidelines for the definition of TNBC.

          -  Subjects must have the ability to understand and the willingness to sign a written
             informed consent document.

        Exclusion Criteria:

          -  Subjects who have had chemotherapy or radiotherapy within 3 weeks (4 weeks for
             immunotherapy; 6 weeks for nitrosoureas or mitomycin C) prior to starting the study
             agent.

          -  Subjects with active brain metastases.

          -  Subjects may not be receiving any other investigational agents or have participated in
             any other clinical trial involving another investigational agent for treatment of
             advanced solid tumors or lymphoma within 3 weeks prior to cycle 1, day 1 of the study.

          -  Subjects who had major surgery or radiation therapy within 4 weeks of the first dose
             of study drug, except for palliative radiotherapy to a limited field, such as for the
             treatment of bone pain or a focally painful tumor mass.

          -  Subjects with a history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to IACS-010759.

          -  Subjects receiving metformin or other agents known to increase risk of lactic
             acidosis.

          -  Subjects who previously received IACS-010759 or oxidative phosphorylation (OXPHOS)
             inhibitors.

          -  Subjects with uncontrolled intercurrent illness including, but not limited to ongoing
             or active serious bacterial, fungal or viral infection or psychiatric illness/social
             situations that would limit compliance with study requirements.

          -  Subjects with a history of significant cardiac disease including: congestive heart
             failure requiring therapy; history of myocardial infarction (MI), angina pectoris,
             coronary artery bypass graft (CABG) within 6 months prior to starting study treatment;
             clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete
             left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular
             block, Mobitz type II and third degree AV block); left ventricular ejection fraction
             (LVEF) < 50% evaluated by echocardiogram (ECHO) or multigated acquisition scan (MUGA);
             increased Fridericia's correction formula (QTcF) (> 450 for men and > 470 for women).

          -  Women who are breast-feeding or pregnant as evidenced by positive serum or urine
             pregnancy test performed within 72 hours of first dosing. (Pregnant women are excluded
             from this study because it is not known whether IACS-010759 has the potential for
             teratogenic or abortifacient effects. Because there is an unknown but potential risk
             for adverse events in nursing infants secondary to treatment of the mother with
             IACS-010759 breastfeeding should be discontinued if the mother is treated with
             IACS-010759.)

          -  Subjects with significant gastrointestinal abnormalities that may affect absorption
             (e.g., gastric bypass, short gut syndrome).

          -  Subjects with known human immunodeficiency virus (HIV), acute chronic hepatitis B
             virus surface antigen (HBsAg) or hepatitis C virus. (HIV-positive subjects are
             ineligible because of the potential for pharmacokinetic interactions of antiviral
             therapy with IACS-010759.)

          -  Lactic acid levels > 2 mmol/L and/or serum pH < 7.35 at baseline.

          -  Subjects with other active malignancy in the past 3 years with the exception of
             adequately treated basal cell or squamous cell carcinoma of the skin, in situ cervical
             cancer, or another early stage cancer that in the discretion of the investigator(s) is
             currently in complete remission.

          -  Subjects with >= Common Terminology Criteria for Adverse Events (CTCAE) grade 2
             toxicity (except alopecia) due to prior cancer therapy.

          -  Subjects with any concomitant disease or condition that, in the clinical judgment of
             the treating physician, is likely to prevent the subject from complying with any
             aspect of the protocol or that may put the subject at unacceptable risk.

          -  Subjects with >= grade 1 peripheral neuropathy at screening.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of IACS-010759 in Advanced Cancers
Time Frame:22 days
Safety Issue:
Description:MTD defined as the highest dose studied for which the observed incidence of DLT is less than 33%. Frequencies of toxicities tabulated according to the NCI Common Toxicity Criteria version 4.03.

Secondary Outcome Measures

Measure:Overall Response Rate of IACS-010759 in Advanced Cancers
Time Frame:6 weeks
Safety Issue:
Description:Response evaluated in this study using RECIST 1.1; the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.
Measure:Pharmacodynamic of IACS-010759 in Advanced Cancers
Time Frame:Days 1,2,4,8,11,15,18 of Cycle 1. Days 1,8,15,21 of Cycle 2. Day 21 of Cycles 3 forward, and 30 days after last dose of study drug.
Safety Issue:
Description:Samples used to develop biomarkers that may be used to predict response or resistance to IACS-010759.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Malignant neoplasm of breast
  • Malignant neoplasms of bone and articular cartilage
  • Malignant neoplasms of digestive organs
  • Malignant neoplasms of female genital organs
  • Malignant neoplasms of lip oral cavity and pharynx
  • Malignant neoplasms of male genital organs
  • Malignant neoplasms of mesothelial and soft tissue
  • Malignant neoplasms of respiratory and intrathoracic organs
  • Malignant neoplasms of thyroid and other endocrine glands
  • Malignant neoplasms of urinary tract
  • Malignant neoplasms stated as primary lymphoid haematopoietic
  • IACS-010759

Last Updated