IACS-010759 in Advanced Cancers

NCT03291938 | Completed Phase 1 FDA Drug

• 3 other identifiers: 2017-0023NCI-2018-01042P30CA016672
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Advanced Malignant Solid Neoplasm; Anatomic Stage III Breast Cancer AJCC v8; Anatomic Stage IIIA Breast Cancer AJCC v8; Anatomic Stage IIIB Breast Cancer AJCC v8; Anatomic Stage IIIC Breast Cancer AJCC v8; Anatomic Stage IV Breast Cancer AJCC v8; Estrogen Receptor Negative; HER2/Neu Negative; Metastatic Malignant Solid Neoplasm; Pancreatic Ductal Adenocarcinoma; Progesterone Receptor Negative; Prognostic Stage III Breast Cancer AJCC v8; Prognostic Stage IIIA Breast Cancer AJCC v8; Prognostic Stage IIIB Breast Cancer AJCC v8; Prognostic Stage IIIC Breast Cancer AJCC v8; Prognostic Stage IV Breast Cancer AJCC v8; Recurrent Lymphoma; Refractory Lymphoma; Stage II Pancreatic Cancer AJCC v8; Stage IIA Pancreatic Cancer AJCC v8; Stage IIB Pancreatic Cancer AJCC v8; Stage III Pancreatic Cancer AJCC v8; Stage IV Pancreatic Cancer AJCC v8; Triple-Negative Breast Carcinoma; Unresectable Solid Neoplasm

Outcome Measures

Primary Outcomes (2)

• Incidence of adverse events

  Up to 2 years

• Maximum tolerated dose

  Up to day 21

Secondary Outcomes (3)

• Maximum Plasma concentration of IACS-010759 [Cmax]

  Up to 2 years

• Overall response rate

  Up to 2 years

• Duration of response

  Up to 2 years

Other Outcomes (1)

• Pharmacodynamic and predictive biomarkers of activity of IACS-010759

  Up to 2 years

Study Arms (1)

Treatment (oxidative phosphorylation inhibitor IACS-010759)

EXPERIMENTAL

INDUCTION PHASE: Patients receive oxidative phosphorylation inhibitor IACS-010759 PO QD on days 1-7 of cycle 1 in the absence of disease progression or unacceptable toxicity. MAINTENANCE PHASE: Patients receive oxidative phosphorylation inhibitor IACS-010759 PO QD on days 8 and 15 of cycle 1 and then on days 1, 8, and 15 of subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Oxidative Phosphorylation Inhibitor IACS-010759; Other: Pharmacodynamic Study; Other: Pharmacokinetic Study

Interventions

Oxidative Phosphorylation Inhibitor IACS-010759 DRUG

Given PO

Also known as: IACS-010759, OXPHOS Inhibitor IACS-010759

Treatment (oxidative phosphorylation inhibitor IACS-010759)

Pharmacodynamic Study OTHER

Correlative studies

Also known as: PHARMACODYNAMIC

Treatment (oxidative phosphorylation inhibitor IACS-010759)

Pharmacokinetic Study OTHER

Correlative studies

Also known as: PHARMACOKINETIC, PK Study

Treatment (oxidative phosphorylation inhibitor IACS-010759)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Yap TA, Daver N, Mahendra M, Zhang J, Kamiya-Matsuoka C, Meric-Bernstam F, Kantarjian HM, Ravandi F, Collins ME, Francesco MED, Dumbrava EE, Fu S, Gao S, Gay JP, Gera S, Han J, Hong DS, Jabbour EJ, Ju Z, Karp DD, Lodi A, Molina JR, Baran N, Naing A, Ohanian M, Pant S, Pemmaraju N, Bose P, Piha-Paul SA, Rodon J, Salguero C, Sasaki K, Singh AK, Subbiah V, Tsimberidou AM, Xu QA, Yilmaz M, Zhang Q, Li Y, Bristow CA, Bhattacharjee MB, Tiziani S, Heffernan TP, Vellano CP, Jones P, Heijnen CJ, Kavelaars A, Marszalek JR, Konopleva M. Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials. Nat Med. 2023 Jan;29(1):115-126. doi: 10.1038/s41591-022-02103-8. Epub 2023 Jan 19.

  PMID: 36658425 DERIVED

Related Links

• MD Anderson Cancer Center Website

MeSH Terms

Conditions

Neoplasm Metastasis; Lymphoma; Pancreatic Neoplasms; Triple Negative Breast Neoplasms

Interventions

IACS-010759; Pharmacogenomic Variants

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Breast Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Polymorphism, Genetic; Genetic Variation; Genetic Phenomena

Study Officials

• Timothy A Yap

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 20, 2017
• First Posted: September 25, 2017
• Study Start: November 13, 2017
• Primary Completion: November 23, 2020
• Study Completion: November 23, 2020
• Last Updated: November 24, 2020

Record last verified: 2020-11

Locations

US (1)