Study to Evaluate the Safety and Tolerability of IACS-010759 in Subjects With Advanced Solid Tumors and Lymphoma

Study Description

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Brief Summary:

This clinical research study has 2 parts: dose escalation and dose expansion.

The goal of dose escalation in this clinical research study is to find the recommended dose of IACS-010759 that can be given to patients with advanced solid tumors or lymphoma.

The goal of dose expansion in this clinical research study is to learn if the dose of IACS-010759 found in the dose escalation part of the study is the best dose to use in future studies using IACS-010759 in patients with advanced solid tumors or lymphoma.

The safety of this drug will also be studied.

This is an investigational study. IACS-010759 is not FDA approved or commercially available. It is currently being used for research purposes only. The study doctor can explain how the study drug is designed to work.

Up to 60 participants will take part in this study. All will be enrolled at MD Anderson.

Condition or disease	Intervention/treatment	Phase
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	Drug: IACS-010759	Phase 1

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Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	60 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 1 Study to Evaluate the Safety and Tolerability of IACS-010759 in Subjects With Advanced Solid Tumors and Lymphoma
Actual Study Start Date :	November 13, 2017
Estimated Primary Completion Date :	November 2023
Estimated Study Completion Date :	November 2024

Arms and Interventions

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Arm	Intervention/treatment
Experimental: IACS-010759 - Dose Escalation Cohort; IACS-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.	Drug: IACS-010759; Dose Escalation Starting Dose of IACS-010759 depends on when participant joins this study. In the first cycle, IACS-010759 administered on Days 1-7 during the Escalation Phase. It is possible that a second schedule (5 days on/2 days off intermittent dose schedule) will also be tested. If following that schedule, IACS-010759 taken by mouth one (1) time for 5 days then skipping 2 days before taking IACS-010759 again. Study doctor will tell participant if following this schedule. Participant admitted to the hospital on Day 7 of Cycle 1 for 24 hours and on Day 15 of Cycle 2 for 24 hours. Dose Expansion Cohorts Starting Dose of IACS-010759: Maximum tolerated dose from Dose Escalation Cohort.
Experimental: Breast Cancer - TNBC Expansion Cohort; TNBC 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.	Drug: IACS-010759; Dose Escalation Starting Dose of IACS-010759 depends on when participant joins this study. In the first cycle, IACS-010759 administered on Days 1-7 during the Escalation Phase. It is possible that a second schedule (5 days on/2 days off intermittent dose schedule) will also be tested. If following that schedule, IACS-010759 taken by mouth one (1) time for 5 days then skipping 2 days before taking IACS-010759 again. Study doctor will tell participant if following this schedule. Participant admitted to the hospital on Day 7 of Cycle 1 for 24 hours and on Day 15 of Cycle 2 for 24 hours. Dose Expansion Cohorts Starting Dose of IACS-010759: Maximum tolerated dose from Dose Escalation Cohort.
Experimental: Pancreatic Cancer - PDAC Expansion Cohort; PDAC 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.	Drug: IACS-010759; Dose Escalation Starting Dose of IACS-010759 depends on when participant joins this study. In the first cycle, IACS-010759 administered on Days 1-7 during the Escalation Phase. It is possible that a second schedule (5 days on/2 days off intermittent dose schedule) will also be tested. If following that schedule, IACS-010759 taken by mouth one (1) time for 5 days then skipping 2 days before taking IACS-010759 again. Study doctor will tell participant if following this schedule. Participant admitted to the hospital on Day 7 of Cycle 1 for 24 hours and on Day 15 of Cycle 2 for 24 hours. Dose Expansion Cohorts Starting Dose of IACS-010759: Maximum tolerated dose from Dose Escalation Cohort.
Experimental: Biopsy Expansion Cohort; Biopsy 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.	Drug: IACS-010759; Dose Escalation Starting Dose of IACS-010759 depends on when participant joins this study. In the first cycle, IACS-010759 administered on Days 1-7 during the Escalation Phase. It is possible that a second schedule (5 days on/2 days off intermittent dose schedule) will also be tested. If following that schedule, IACS-010759 taken by mouth one (1) time for 5 days then skipping 2 days before taking IACS-010759 again. Study doctor will tell participant if following this schedule. Participant admitted to the hospital on Day 7 of Cycle 1 for 24 hours and on Day 15 of Cycle 2 for 24 hours. Dose Expansion Cohorts Starting Dose of IACS-010759: Maximum tolerated dose from Dose Escalation Cohort.

Outcome Measures

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Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) of IACS-010759 in Advanced Cancers [ Time Frame: 22 days ]
   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.
2. Adverse Events of IACS-010759 in Advanced Cancers [ Time Frame: Start of study drug up to 2 years after the last dose of drug ]
   Adverse Events reported using the NCI CTCAE Ver 4.03.

Secondary Outcome Measures :

1. Overall Response Rate of IACS-010759 in Advanced Cancers [ Time Frame: 6 weeks ]
   Response evaluated in this study using RECIST 1.1; the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.
2. 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. ]
   Samples used to develop biomarkers that may be used to predict response or resistance to IACS-010759.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Male and non-pregnant females >/= 18 years old
2. Subjects must have histologically confirmed malignancy that is metastatic or unresectable and for which there is no available therapy likely to convey clinical benefit.
3. 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.
4. Subjects must have evaluable disease for the dose escalation, and measurable disease for the dose expansion
5. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
6. Subjects must have a life expectancy >/= 12 weeks.
7. Subjects must have normal organ and marrow function as defined below: absolute neutrophil count >/= 1,500/mcL; hemoglobin >/= 9 g/dL; platelets >/= 100,000/mcL; total bilirubin </= 1.5X the institutional upper limit of normal (ULN); aspartate transaminase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine transaminase (ALT) serum glutamic pyruvic transaminase (SGPT) </= 2.5X institutional ULN or </= 5X 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.
8. 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;
9. (Incl #8 Cont'd) 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
10. (Incl #8 Cont'd) 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.
11. (Incl #8 Cont'd) Note: 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.
12. 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.
13. 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.
14. 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.
15. Subjects who enroll in the TNBC dose expansion cohort should adhere to the ASCP/CAP guidelines for the definition of TNBC
16. Subjects must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. 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.
2. Subjects with active brain metastases.
3. 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.
4. 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
5. Subjects with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to IACS-010759.
6. Subjects receiving metformin or other agents known to increase risk of lactic acidosis.
7. Subjects who previously received IACS-010759 or OXPHOS inhibitors.
8. 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.
9. 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 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 QTcF (>450 for men and >470 for women)
10. 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.)
11. Subjects with significant gastrointestinal abnormalities that may affect absorption (e.g., gastric bypass, short gut syndrome).
12. 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.)
13. Lactic acid levels > 2 mmol/L and/or serum pH <7.35 at screening.
14. 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.
15. Subjects with >/= Common Terminology Criteria for Advance Events (CTCAE) grade 2 toxicity (except alopecia) due to prior cancer therapy.
16. 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.

Contacts and Locations

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Contacts

Contact: Timothy A. Yap, PHD, MBBS	713-563-1784	CR_Study_Registration@mdanderson.org

Locations

United States, Texas
University of Texas MD Anderson Cancer Center	Recruiting
Houston, Texas, United States, 77030
Contact: Clinical Research Operations CR_Study_Registration@mdanderson.org

Sponsors and Collaborators

M.D. Anderson Cancer Center

Investigators

Principal Investigator:	Timothy A. Yap, PHD, MBBS	M.D. Anderson Cancer Center

More Information

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Additional Information:

University of Texas MD Anderson Cancer Center Website 

Responsible Party:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT03291938 History of Changes
Other Study ID Numbers:	2017-0023; NCI-2018-01042 ( Registry Identifier: NCI CTRP )
First Posted:	September 25, 2017
Last Update Posted:	May 30, 2018
Last Verified:	May 2018

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by M.D. Anderson Cancer Center:

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

Additional relevant MeSH terms:

Neoplasms; Breast Neoplasms; Genital Neoplasms, Female; Urologic Neoplasms; Genital Neoplasms, Male; Lip Neoplasms; Bone Neoplasms; Thyroid Neoplasms; Cartilage Diseases; Soft Tissue Neoplasms; Neoplasms, Fibrous Tissue; Neoplasms by Site; Breast Diseases; Skin Diseases; Urogenital Neoplasms	Genital Diseases, Male; Mouth Neoplasms; Head and Neck Neoplasms; Lip Diseases; Mouth Diseases; Stomatognathic Diseases; Bone Diseases; Musculoskeletal Diseases; Endocrine Gland Neoplasms; Endocrine System Diseases; Thyroid Diseases; Connective Tissue Diseases; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type