Phase I, First-in-Human, Open-Label, Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of M4112 an IDO1/TDO2 Inhibitor as Single Agent and Sequentially in Combinations with Avelumab or M7824 (TGFß Trap) in Subjects with Metastatic or Locally Advanced Unresectable Solid Tumors

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There are 2 parts to this study: Part 1 and Part 2. This consent form is for Part 1 only. In Part 1, there are 3 sub-groups: Part 1A, 1B, and 1C. The goal of this clinical research study is to find the highest tolerable dose of M4112 that can be given to patients with advanced or metastatic (have spread) solid tumors that are unresectable (cannot be removed with surgery). In this study, M4112 will be studied alone (Part 1A) or in combination with either avelumab (Part 1B) or M7824 (Part 1C). This is the first study using M4112 in humans. The safety of M4112 and the drug combinations will also be studied.

General Information

Disease Group: Malignant neoplasms of ill-defined secondary and unspecified sites,Malignant neoplasms of independent (primary) multiple sites

Treatment Agent: Avelumab,M4112,MSB0011359C

Treatment Location: Both at MDACC & and Other Sites

Sponsor: EMD Serono

Study Objectives/Outcome

Primary Objectives Part IA (Dose Escalation – M4112 as Single Agent) To determine safety and tolerability or, if observed, the maximum tolerated dose (MTD), and to define the recommended phase 2 dose (RP2D) of M4112 as single agent in subjects with solid tumors. Part IB (Dose Escalation – M4112 in Combination with Avelumab) To determine safety and tolerability or, if observed, the MTD, and to define the RP2D of M4112 in combination with avelumab in subjects with solid tumors. Part IC (Dose Escalation – M4112 in Combination with M7824) To determine safety and tolerability or, if observed, the MTD, and to define the RP2D of M4112 in combination with M7824 in subjects with solid tumors. Secondary Objectives Part IA (Dose Escalation – M4112 as Single Agent) To characterize the pharmacokinetic (PK) parameters of M4112 as single agent. To assess QT prolongation potential by central tendency, outlier analysis and the slope of exposure-QT corrected interval (QTc) analysis to evaluate preliminary clinical activity parameters using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. To evaluate preliminary clinical activity parameters using RECIST 1.1. Part IB (Dose Escalation – M4112 in Combination with Avelumab) To characterize the PK parameters of M4112 and avelumab exposure in combination. To evaluate the immunogenicity of avelumab when given in combination with M4112. To evaluate preliminary clinical activity parameters using RECIST 1.1. Part IC (Dose Escalation – M4112 in Combination with M7824) To characterize the PK parameters of M4112 and M7824 exposure in combination. To evaluate the immunogenicity of M7824 when given in combination with M4112. To evaluate preliminary clinical activity parameters using RECIST 1.1. Exploratory Objectives Part IA (Dose Escalation – M4112 as Single Agent) To evaluate the effect of M4112 on kynurenine (Kyn) and tryptophan (Trp) in plasma of subjects. To evaluate the effect of M4112 on indoleamine-2,3-dioxygenase 1 (IDO1) activity in ex vivo stimulated whole blood of subjects. To study genetic variations that may affect the safety and tolerability, PK and pharmacodynamics (PD) profiles of M4112. To evaluate the effects of M4112 on changes in immune phenotype and cytokines in relation to treatment-related adverse events (TRAE) and clinical outcomes. To assess effects of M4112 as single agent on 4B-hydroxycholesterol and cholesterol activity. Part IB (Dose Escalation – M4112 in Combination with Avelumab) To evaluate the effect of M4112 in combination with avelumab on Kyn and Trp in plasma of subjects. To evaluate the effect of M4112 on IDO1 activity in ex vivo stimulated whole blood of subjects. To study genetic variations that may affect the safety and tolerability, PK and PD profiles of M4112 in combination with avelumab. To evaluate the effects of M4112 in combination with avelumab on changes in immune phenotype and cytokines in relation to TRAE and clinical outcomes. Part IC (Dose Escalation – M4112 in Combination with M7824) To evaluate the effect of M4112 in combination with M7824 on Kyn and Trp in plasma of subjects. To evaluate the effect of M4112 on IDO1 activity in ex vivo stimulated whole blood of subjects. To study genetic variations that may affect the safety and tolerability, PK and PD profiles of M4112 in combination with M7824. To evaluate the effects of M4112 in combination with M7824 on changes in immune phenotype and cytokines in relation to TRAE and clinical outcomes.

IRB Review and Approval Date: 12/11/2017

Recruitment Status: Open

Projected Accrual: 60

Enrollment Eligibility
Eligibility:

1) Signed written informed consent form (ICF) before any study-related procedure is undertaken that is not part of the standard subject management.
2) Male or female subjects >/= 18 years of age.
3) Subject population: a. In the dose escalation cohorts (Part IA to Part IC): Histologically or cytologically proven advanced or metastatic solid malignancies for whom no effective standard therapy exists or has failed or subjects who are intolerant to established therapy known to provide clinical benefit for their condition.
4) Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at Screening.
5) Subjects who have been treated previously with a checkpoint inhibitor may enroll.
6) Adequate hematological function as defined below: a. Absolute neutrophil count >/= 1,500/mm^3 or >/= 1.5 × 10^9/L; b. Platelet count >/= 100,000/mm^3 or >/= 100 × 10^9/L; c. Hemoglobin >/= 9 g/dL.
7) Adequate hepatic function defined: by a total bilirubin level 1.5 × ULN but < 3 × ULN; b. Subjects with tumor involvement in their liver: AST < 3.0 × ULN, ALT < 3.0 × ULN, with normal bilirubin 8) Adequate renal function defined by an estimated glomerular filtration rate > 50 mL/min according to the Cockcroft-Gault formula or normal creatinine laboratory values. (Glomerular filtration rate [mL/min/1.73 m^2] = 175 × serum creatinine (Scr)-1.154 × age – 0.203 × 1.212 [if African American] × 0.742 [if female]).
9) Male participants must agree to use and to have their female partners use a highly effective contraception (i.e., methods with a failure rate of less than 1 % per year) as detailed in protocol 30 days before first dose of study treatment (as appropriate), during the treatment period and for at least 60 days after the last dose of study treatment of M4112 as single agent or in combination with avelumab and for at least 120 days after the last dose of M7824 and must refrain from donating sperm during this period.
10) Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in protocol, OR b. A WOCBP who agrees to use a highly effective contraception (i.e., methods with a failure rate of less than 1 % per year) as detailed in protocol 30 days before start of first dose of study treatment (as appropriate), during the treatment period and for at least 60 days after the last dose of study treatment of M4112 as single agent or in combination with avelumab and for at least 120 days after the last dose of M7824. Since the effect of potential of M4112 to induce/inhibit CYP3A4 is unknown at this time, WOCBP that are currently using hormonal contraception that is a substrate for CYP3A4 should also use double barrier contraception.
11) Women of childbearing potential must have a negative plasma pregnancy test at the Screening Visit and a negative urine pregnancy test on Day 1 before enrollment and dosing.
Exclusion:

1) Prior therapy with: In combination with avelumab or M7824 in the dose escalation only cohorts (Part 1B and Part 1C): Intolerance to immune checkpoint inhibitor therapy as defined by the occurrence of an adverse drug reaction (ADR) requiring drug discontinuation.
2) Persisting toxicity related to prior therapy Grade > 1 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 4.03, however sensory neuropathy Grade 3) Prior organ transplantation including allogeneic stem cell transplantation.
4) All subjects with known brain metastases, except those meeting the following criteria: a. Brain metastases that have been treated locally and are clinically stable for at least 4 weeks prior to the start of treatment. b. No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable). c. Subjects must be either off steroids or on a stable or decreasing dose of < 10 mg daily prednisone (or equivalent).
5) Concurrent treatment with a non-permitted drug/intervention: a. Strong inhibitors or inducers of CYP3A4, and drugs with a narrow therapeutic index, which are predominantly metabolized by CYP3A4 should be discontinued 7 days prior to treatment and avoided during treatment. b. Drugs known to have a high risk of prolonging QTc as per label. c. Drugs that are known to increase gastric pH should be stopped at least 1 week before the start of study treatment.
6) Continued from #5: d. Anticancer treatment (eg, cytoreductive therapy, radiotherapy, immune therapy, cytokine therapy, monoclonal antibody, targeted small molecule therapy) or any investigational drug within 4 weeks prior to start of study treatment, or not recovered from adverse event (AE) related to such therapies, with the following exceptions: i. Palliative bone-directed radiotherapy is permitted (concurrently or within pretreatment period). ii. Hormonal therapies acting on the hypothalamic-pituitary-gonadal axis are permitted (ie, luteinizing hormone-releasing hormone agonist/antagonists). No other hormonal anticancer therapy is permitted. e. Major surgery (as deemed by the Investigator) for any reason, except diagnostic biopsy, within 4 weeks of the study treatment and/or if the subject has not fully recovered from the surgery within 4 weeks of the study treatment.
7) Continued from #5: f. Subjects receiving immunosuppressive agents (such as steroids), for any reason, should be tapered off these drugs before start of study treatment, with the following exceptions: i. Subjects with adrenal insufficiency, may continue corticosteroids at physiologic replacement dose, equivalent to < 10 mg prednisone daily. ii. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation). iii. Previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon is acceptable as long as it is anticipated that the administration of steroids will be completed in 14 days, or that the dose after 14 days will be equivalent to 8) Current significant cardiac conduction abnormalities, including corrected QT interval (QTc) prolongation of > 450 milliseconds or impaired cardiovascular function, ventricular tachycardia, hypokalemia or a history of paroxysmal atrial fibrillation, serious cardiac arrhythmia and family history of sudden death or long QT syndrome.
9) A history of cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina or congestive heart failure (New York Heart Association Classification Class >/= II).
10) Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: a. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible. b. Autoimmune diseases: eg, inflammatory bowel diseases, interstitial lung disease or pulmonary fibrosis.
11) Pneumonitis and history of pneumonitis.
12) A history of difficulty of swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastro-intestinal disease or conditions that may hamper compliance and/or absorption of the M4112.
13) Any psychiatric condition that would prohibit the understanding or rendering of Informed Consent, or interfere with compliance to study requirements and procedures in the opinion of Investigator and/or Sponsor.
14) Known current alcohol and drug abuse as determined by the Investigator if no consent by legal representative.
15) Hepatocellular carcinoma.
16) Legal incapacity or limited legal capacity.
17) Significant acute or chronic infections requiring systemic therapy including, among others: a. History of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. b. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as, HBV surface antigen positive and HBV core antibody positive with reflex to positive HBV DNA or HBV core antibody positive alone with reflex to positive HBV DNA or positive HCV antibody with reflex to positive HCV RNA). Subjects with a history of infection must have polymerase chain reaction documentation that infection has cleared. c. Active tuberculosis (history of exposure or history of positive TB test with presence of clinical symptoms, physical, or radiographic findings).
18) Known hypersensitivity to the investigational medicinal products (IMPs) or to one or more of the excipients of M4112, avelumab or M7824.
19) Known severe hypersensitivity reactions to monoclonal antibodies (Grade >/= 3 NCI-CTCAE 4.03), or uncontrolled asthma (ie, 3 or more features of partially controlled asthma).
20) Pregnancy or lactation.
21) Administration of a live vaccine within 28 days prior to study entry.
For Enrollment:

713-563-1930