First-in-Human Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of M1069 in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- M1069
- Conditions
- Metastatic or Locally Advanced Unresectable Solid Tumors
- Sponsor
- EMD Serono Research & Development Institute, Inc.
- Enrollment
- 15
- Locations
- 5
- Primary Endpoint
- Safety Profile as Assessed by Incidence of Adverse Events (AEs), Treatment-Related AEs and Dose-Limiting Toxicities (DLTs)
- Status
- Terminated
- Last Updated
- 10 days ago
Overview
Brief Summary
The main purpose of this study was to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and early signs of efficacy of M1069 in participants with advanced solid malignancies.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants who had histologically or cytologically proven locally advanced or metastatic solid malignancies and who are refractory to or have progressed under standard treatment or for whom standard treatment is not expected to deliver clinical benefit
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at Screening
- •Adequate hematological function, hepatic function and renal function
- •Ability to swallow oral dose forms (for example \[e.g.\] capsules)
- •Fresh tumor biopsies mandatory for participants at Dose level 2 (DL2) and 6 participants upon potential determination of Recommended Dose for Expansion (RDE). Providing consent to fresh tumor biopsies taken during the Screening period and an on-treatment biopsy is mandatory
- •Life expectancy of at least 12 weeks according to Investigator judgement
- •Measurable disease according to The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
- •Other protocol defined inclusion criteria could apply
Exclusion Criteria
- •Persisting toxicity related to prior therapy Grade greater than (\>) 1 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, however, alopecia, sensory neuropathy hypothyroidism and diabetes mellitus Grade less than or equal to (\<=) 2, despite treatment, are allowed
- •Prior organ transplantation including allogeneic stem cell transplantation
- •Participants 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)
- •Participants must be either off steroids or on a stable or decreasing dose of \< 10 milligrams (mg) daily prednisone (or equivalent)
- •Current significant cardiac conduction abnormalities, including corrected QT interval (QTcF, corrected with Fridericia formula) prolongation of \> 470 milliseconds (ms) or impaired cardiovascular function, ventricular tachycardia (including Torsades de Pointes), or a history of paroxysmal atrial fibrillation, serious cardiac arrhythmia and family history of sudden death or long QT syndrome
- •Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent including but not limited to inflammatory bowel diseases, autoimmune hepatitis, interstitial lung disease of immunologic origin, systemic lupus erythematosus, et cetera (etc.), with the following exceptions: a) Participants with diabetes type I, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
- •Significant acute or chronic fungal, bacterial and/or viral infections requiring systemic therapy including coronavirus disease of 2019 (COVID-19)
- •Known hypersensitivity to the trial treatment or to one or more of the excipients
- •Other protocol defined exclusion criteria could apply
Arms & Interventions
M1069
Intervention: M1069
Outcomes
Primary Outcomes
Safety Profile as Assessed by Incidence of Adverse Events (AEs), Treatment-Related AEs and Dose-Limiting Toxicities (DLTs)
Time Frame: Time from first dose of study drug up to planned assessment at 18.2 months
Number of Participants With Dose-Limiting Toxicities (DLTs)
Time Frame: Cycle 1 (first 21 days after first study drug administration)
A DLT was defined as any AE, per National Cancer Institute - Common Terminology Criteria for Adverse Events, Version 5.0 (NCI-CTCAE v5.0), assessed by the Investigator or Sponsor at any dose, unrelated to underlying disease, prior/concomitant medication, or condition, occurring during the DLT observation period. DLTs included Grade more than equal to (≥) 3 thrombocytopenia with bleeding, excluding isolated Grade 4 lymphopenia without symptoms or Grade 4 neutropenia/thrombocytopenia less than (\<) 7 days without signs. Other DLTs were Hy's Law hepatotoxicity without clear cause, vision changes (≥5-line Best Corrected Visual Acuity (BCVA) loss, BCVA \<20/160, MD \>9 decibel (dB), macular thickness \>25 percentage (%)), severe eye disorders limiting self-care, ≥5-day drug interruption to prevent DLT.
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment Related TEAEs and Serious TEAEs
Time Frame: Up to 16 months
An AE can be any unfavorable and unintended sign, symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. For surgical or diagnostic procedures, the condition/illness leading to such a procedure is considered as the AE rather than the procedure itself. An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration. TEAEs included both serious TEAEs and non-serious TEAEs. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization, results in persistent disability. Treatment Related TEAEs are also reported.
Secondary Outcomes
- Pharmacokinetic (PK) Plasma Concentrations of M1069(Pre-dose up to 24 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8 (each cycle is of 21 days))
- Change from Baseline in Tumor Microenvironment (TME) in Available Paired Tumor Biopsies at Cycle 2 Day 15(Baseline, Cycle 2 Day 15 (each cycle is of 21 days))
- Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), as Assessed by Investigator(Time from first dose of study drug up to planned assessment at 18.2 months)
- Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), as Assessed by Investigator(Time from first dose of study drug up to planned assessment at 18.2 months)
- Duration of Response (DoR)(Time from first dose of study drug up to planned assessment at 18.2 months)
- Pharmacodynamic Assessment by Phosphorylated cAMP Response Element-binding Protein (pCREB) Level in ex-vivo Stimulated Blood(Pre-dose up to 8 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8; Pre-dose on Cycle 2 Day 1 (each cycle is of 21 days))
- Change from Baseline in Corrected QT (QTc) Interval Over Time(Pre-dose (Baseline) up to 8 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8 (each cycle is of 21 days))
- Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of M1069(Day 8 and 15 of Cycle 1 and Day 1 of Cycle 4 (each cycle is of 21 days))
- Area Under Plasma Concentration Time Curve From Time Zero to 24, Divided by Dose (AUC [0-24]/D) of M1069(Day 8 and 15 of Cycle 1 and Day 1 of Cycle 4 (each cycle is of 21 days))
- Maximum Observed Plasma Concentration (Cmax) of M1069(Day 8 and 15 of Cycle 1 and Day 1 of Cycle 4 (each cycle is of 21 days))
- Maximum Observed Plasma (Peak) Drug Concentration, by Dose (Cmax/D)(Day 8 and 15 of Cycle 1 and Day 1 of Cycle 4 (each cycle is of 21 days))
- Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax)(Day 8 and 15 of Cycle 1 and Day 1 of Cycle 4 (each cycle is of 21 days))
- Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), as Assessed by Investigator(Time from first observation of response (CR or PR) up to planned assessment at 17.3 months)
- Duration of Response (DoR)(Time from first observation of response (CR or PR) up to planned assessment at 17.3 months)
- Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), as Assessed by Investigator(Time from first administration of study intervention to the date of the first documentation of progression disease (PD) or death due to any cause within, whichever occurs first, assessed up to maximum of 17.3 months)
- Change From Baseline in Corrected QT (QTc) Interval(Cycle (C)1Day (D)1: 1h, 2h, 4h, 6h, 8h post-dose; C1D8: 15min predose, 1h, 2h, 4h, 6h, 8h post-dose; C1D15: predose; C2D1: predose, 2h post-dose; C4D1, C6D1, C10D1, C12D1, C14D1, C18D1(each cycle is of 21 days))