MedPath

Study of Avelumab-M3814 Combinations

Phase 1
Completed
Conditions
Oncology
Solid Tumors
Interventions
Radiation: Radiotherapy
Registration Number
NCT03724890
Lead Sponsor
EMD Serono Research & Development Institute, Inc.
Brief Summary

The main purpose of the study was to evaluate a safe, tolerable recommended Phase II dose (RP2D) and/or the maximum tolerated dose (MTD) of M3814 when given in combination with avelumab with and without radiotherapy in participants with selected advanced solid tumors.

Detailed Description

Not available

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
57
Inclusion Criteria
  • Part A and Part FE (M3814 + avelumab): Participants had histologically or cytologically proven advanced or metastatic solid tumors for which no standard therapy exists, standard therapy has failed, or participants are intolerant to or have rejected established therapy known to provide clinical benefit for their condition
  • Part B (M3814 + Radiotherapy [RT] + avelumab): histologically or cytologically proven advanced or metastatic solid tumors for which no standard therapy exists, standard therapy has failed, or participants are intolerant to or have rejected established therapy known to provide benefit for their condition and are amenable to receive RT
  • Part A, B and FE: Measurable or evaluable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v 1.1)
  • Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 at study entry
  • Part A, B and FE: Female participants of childbearing potential should be willing to use a highly effective contraceptive method
  • Part A, B and FE: Male participants should agree to refrain from donating sperm plus, either: abstain from any activity that allows for exposure to ejaculate
  • Use an adequate method of contraception starting with the first dose of study therapy through 90 days after the last dose of study therapy
  • Part A, B and FE: Be willing to provide informed consent for the trial
  • Other protocol defined inclusion criteria could apply
Exclusion Criteria
  • Participants who had received prior chemotherapy, hormonal anticancer therapy with the exception of luteinizing hormone-releasing hormone analogs, biologic therapy, or any other anticancer therapy within 28 days of the first dose of study treatments (6 weeks for nitrosoureas or mitomycin C)
  • Participants who had undergone major surgery for any reason, except diagnostic biopsy, within 4 weeks of the study intervention and/or has not fully recovered from the surgery within 4 weeks of the study intervention
  • Participants with evidence of active or history of autoimmune disease that might deteriorate when receiving an immune-stimulatory agent
  • Participants with brain metastases, except those meeting the following criteria: a) brain metastases that have been treated locally and are clinically stable for greater than or equal to (>=) 4 weeks prior to randomization 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) participants must be either off steroids or on a stable or decreasing dose of less than (<) 10 milligrams (mg) daily prednisone (or equivalent)
  • Participants with severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year), psychiatric or substance abuse disorders; or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study intervention administration or may interfere with the interpretation of study results
  • Participants requiring systemic immunosuppressive agents (such as steroids) for any reason who cannot be tapered off these drugs before start of study intervention, with the following exceptions: a) participants with adrenal insufficiency, may continue corticosteroids at physiologic replacement dose, equivalent to less than or equal to (<=) 10 mg prednisone daily b) participants requiring steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) is permitted c) participants with previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon planned to be completed in 14 days, or that the dose after 14 days will be equivalent to <= 10 mg prednisone daily
  • Participants with a history of human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome, Hepatitis B virus or Hepatitis C and with history of infection must have a polymerase chain reaction (PCR) documentation that infection is cleared
  • Participants who had received a live vaccine within 30 days prior to the first dose of trial treatment
  • Participants with known prior severe hypersensitivity to any of the investigational products or any component in its formulations
  • Participants with evidence of additional malignancy within the last 5 years unless a complete remission without further recurrence was achieved at least 2 years prior to study entry and participants were deemed to have been cured with no additional therapy required or anticipated to be required. Participants with treated nonmelanoma skin cancers, carcinoma in situ of skin, bladder, cervix, colon/rectum, breast, or prostate may participate
  • Participants pretreated with immunotherapy who have, any history of dose limiting toxicities (DLTs) with prior immunotherapy agents, including Grade 3/4 immune-related adverse events (irAEs); irreversible irAEs; Grade greater than or equals to (>=) 3 irAEs that did not respond to steroid rescue; or neurologic irAE with significant clinical sequelae
  • Participants with irAE requiring hormone replacement therapy (e.g., thyroxine, insulin, or physiologic dose of corticosteroid replacement therapy for adrenal or pituitary insufficiency) may participate as long as the endocrinopathy is well controlled and the participant is not otherwise symptomatic from hormone insufficiency
  • Physiologic corticosteroid dose is defined as <= 10 mg daily of prednisone or equivalent
  • for Part B only:
  • Participants who had confirmed esophagitis and in whom radiation planning target volume will include any portion of the esophagus, the participant is not eligible unless an esophageal endoscopy rules out the presence of esophagitis
  • Participants in whom more than 10 percent (%) of the total esophagus volume might receive more than 15 gray (Gy) (50% of the prescribed radiotherapy [RT] dose)
  • Participants who have had previous radiotherapy to the same region as intended to be irradiated in this study within the past 12 months
  • Participants who had had extensive previous radiotherapy on >= 30% of bone marrow reserve or prior bone marrow/stem cell transplantation within 5 years before study start
  • If participant hepatic metastatic lesion is selected to be irradiated: - the non-tumor liver volume < 700 milli liters (mL); - Child-Pugh score >= 8
  • Other protocol defined exclusion criteria could apply

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Part A: M3814 + AvelumabM3814-
Part A: M3814 + AvelumabAvelumab-
Part B: M3814 + Avelumab + Radiotherapy (RT)M3814-
Part B: M3814 + Avelumab + Radiotherapy (RT)Avelumab-
Part B: M3814 + Avelumab + Radiotherapy (RT)Radiotherapy-
Part FE: M3814 + Avelumab (fasted/fed state)M3814-
Part FE: M3814 + Avelumab (fasted/fed state)Avelumab-
Primary Outcome Measures
NameTimeMethod
Part FE: Maximum Observed Plasma Concentration (Cmax) of M3814Pre-dose, 1, 2, 4 and 6 hours post-dose on Day 1; Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15; Pre-dose, 2, 4 and 6 hours post-dose on Day 22

Cmax was obtained directly from the concentration versus time curve.

Part A: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0Day 1 up to Day 21

A DLT was defined as any Grade more than or equal to \>= 3 nonhematologic Adverse Event(AE) or any Grade\>= 4 hematologic,, occurring during the DLT period that is related to any of the study interventions. In addition, a DLT is considered: Grade 3 thrombocytopenia with medically concerning bleeding, Any febrile neutropenia. A study intervention-related Treatment emergent Adverse Event(TEAE) is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk. Any toxicity related to study intervention that causes the participant to receive less than 80% of M3814 during DLT period, evidence of study treatment-related hepatocellular injury for more than 3 days, such as\> 5-fold elevations above the Upper Limits of Normal (ULN) of Alanine Aminotransferase (ALT) or Aspartate Aminotransferase(AST) with or without elevation of serum total bilirubin to \> 2 × ULN. Number of Participants with DLT Grade \>= 3 were reported.

Part B: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0Day 1 up to Day 28

A DLT was defined as any Grade more than or equal to \>= 3 nonhematologic Adverse Event(AE) or any Grade\>= 4 hematologic,, occurring during the DLT period that is related to any of the study interventions. In addition, a DLT is considered: Grade 3 thrombocytopenia with medically concerning bleeding, Any febrile neutropenia. A study intervention-related Treatment emergent Adverse Event(TEAE) is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk. Any toxicity related to study intervention that causes the participant to receive less than 80% of M3814 during DLT period, evidence of study treatment-related hepatocellular injury for more than 3 days, such as\> 5-fold elevations above the Upper Limits of Normal (ULN) of Alanine Aminotransferase (ALT) or Aspartate Aminotransferase(AST) with or without elevation of serum total bilirubin to \> 2 × ULN. Number of Participants with DLT Grade \>= 3 were reported.

Part Food Effect (FE): Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to 6 Hour (AUC0-6hour) of M3814Pre-dose, 1, 2, 4 and 6 hours post-dose on Day 1; Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15; Pre-dose, 2, 4 and 6 hours post-dose on Day 22

Area under the plasma concentration versus time curve from time zero to 6 hours post dosing for M3814 was reported.

Secondary Outcome Measures
NameTimeMethod
Part A: Average Plasma Concentration of M3814 Observed Post-dose (Cavg)Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1

Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve.

Part B: Average Plasma Concentration of M3814 Observed Post-dose (Cavg)Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1

Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve.

Part A: Fluctuation Index of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1

Fluctuation index is defined as percentage fluctuation (variation between maximum and minimum concentration at steady state), calculated as: 100\*(\[Cmax Cmin\]/Cavg).

Part B: Fluctuation Index of M3814Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1

Fluctuation index is defined as percentage fluctuation (variation between maximum and minimum concentration at steady state), calculated as: 100\*(\[Cmax Cmin\]/Cavg).

Part B: Accumulation Ratio of AUC [Racc (AUC 0-24)] of M3814Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1; Pre-dose, 2, 4 and 6 hours post-dose on Day 10

Accumulation ratio of AUC0-12 was calculated as AUC0-t, after dosing on Day 10 divided by AUC0-t, after dosing on Day 1.

Part B: Accumulation Ratio of Cmax [Racc(Cmax)] of M3814Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1;Pre-dose, 2, 4 and 6 hours post-dose on Day 10

Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 10 divided by Cmax, after dosing on Day 1.

Part A: Accumulation Ratio of AUC [Racc (AUC 0-12)] of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Days 1 and 15

Accumulation ratio of AUC0-12 was calculated as AUC0-t, after dosing on Day 15 divided by AUC0-t, after dosing on Day 1.

Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0Time from first study intervention up to long term safety follow-up period (Up to 516 days)

An Adverse Event(AE) is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign, symptom, or disease associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to study intervention. Number of participants with TEAEs, treatment related TEAEs and serious TEAEs were reported.

Part A: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)Time from first study intervention up to long term safety follow-up period (Up to 516 days)

Number of participants with clinically meaningful change from baseline in ECG parameters were reported. Clinically Meaningful Change was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula.

Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0Time from first study intervention up to long term safety follow-up period (Up to 513 Days)

An Adverse Event(AE) is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign, symptom, or disease associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to study intervention. Number of participants with TEAEs, treatment related TEAEs and serious TEAEs were reported.

Part FE: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0Time from first study intervention up to long term safety follow-up period (Up to 404 Days)

An Adverse Event(AE) is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign, symptom, or disease associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to study intervention. Number of participants with TEAEs, treatment related TEAEs and serious TEAEs were reported.

Part A: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test ValuesTime from first study intervention up to long term safety follow-up period (Up to 516 days)

The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with abnormalities Grade \>= 3 in laboratory test values were reported.

Part B: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test ValuesTime from first study intervention up to long term safety follow-up period (Up to 513 Days)

The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with abnormalities Grade \>= 3 in laboratory test values were reported.

Part FE: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test ValuesTime from first study intervention up to long term safety follow-up period (Up to 404 Days)

The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with abnormalities Grade \>= 3 in laboratory test values were reported.

Part B: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)Time from first study intervention up to long term safety follow-up period (Up to 513 Days)

Number of participants with clinically meaningful change from baseline in ECG parameters were reported. Clinically Meaningful Change was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula.

Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)Time from first study intervention up to long term safety follow-up period (Up to 404 Days)

Number of participants with clinically meaningful change from baseline in ECG parameters were reported. Clinically Meaningful Change was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula.

Part A: Number of Participants With Clinically Meaningful Change From Baseline in Vital SignsTime from first study intervention up to long term safety follow-up period (Up to 516 days)

Number of participants with clinically meaningful change from baseline in vital signs. Clinically Meaningful Change was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate.

Part B: Number of Participants With Clinically Meaningful Change From Baseline in Vital SignsTime from first study intervention up to long term safety follow-up period (Up to 513 Days)

Number of participants with clinically meaningful change from baseline in vital signs. Clinically Meaningful Change was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate.

Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Vital SignsTime from first study intervention up to long term safety follow-up period (Up to 404 Days)

Number of participants with clinically meaningful change from baseline in vital signs. Clinically Meaningful Change was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate.

Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline ScoreTime from first study intervention up to long term safety follow-up period (Up to 516 days)

ECOG PS score is widely used by doctors and researchers to assess how a participants disease is progressing and is used to assess how the disease affects the daily living abilities of the participant and determine appropriate treatment and prognosis. The score ranges from Grade0 to Grade5, where Grade0=Fully active, able to carry on all pre-disease performance without restriction, Grade1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade5=Death.ECOG performance status was reported in terms of number of participants with baseline value vs worst post-baseline value.

Part A: Accumulation Ratio of Maximum Observed Drug Concentration [Racc(Cmax)] of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Days 1 and 15

Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on Day 1.

Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline ScoreTime from first study intervention up to long term safety follow-up period (Up to 513 Days)

ECOG PS score is widely used by doctors and researchers to assess how a participants disease is progressing and is used to assess how the disease affects the daily living abilities of the participant and determine appropriate treatment and prognosis. The score ranges from Grade0 to Grade5, where Grade0=Fully active, able to carry on all pre-disease performance without restriction, Grade1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade5=Death.ECOG performance status was reported in terms of number of participants with baseline value vs worst post-baseline value.

Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline ScoreTime from first study intervention up to long term safety follow-up period (Up to 404 Days)

ECOG PS score is widely used by doctors and researchers to assess how a participants disease is progressing and is used to assess how the disease affects the daily living abilities of the participant and determine appropriate treatment and prognosis. The score ranges from Grade0 to Grade5, where Grade0=Fully active, able to carry on all pre-disease performance without restriction, Grade1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade5=Death.ECOG performance status was reported in terms of number of participants with baseline value vs worst post-baseline value.

Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1

Cmax was obtained directly from the concentration versus time curve.

Part A: Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15

Cmax was obtained directly from the concentration versus time curve.

Part B: Single Dose: Maximum Observed Drug Concentration (Cmax) of M3814Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1

Cmax was obtained directly from the concentration versus time curve.

Part B: Multiple Dose: Maximum Observed Drug Concentration (Cmax) of M3814Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 10

Cmax was obtained directly from the concentration versus time curve.

Part A: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15

Tmax was obtained directly from the concentration versus time curve.

Part A: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15

Tmax was obtained directly from the concentration versus time curve.

Part B: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814Pre-dose, 2, 4 and 6 hours post-dose on Day 10

Tmax was obtained directly from the concentration versus time curve postdose.

Part B: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814Pre-dose, 2, 4 and 6 hours post-dose on Day 10

Tmax was obtained directly from the concentration versus time curve postdose.

Part A: Minimum Observed Drug Concentration (Cmin) of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1

Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.

Part B: Minimum Observed Drug Concentration (Cmin) of M3814Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1

Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.

Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1

Area under the serum concentration-time curve (AUC) from time zero to the last sampling time point at which the concentration is at or above lower limit of quantification (LLOQ).

Part B: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M3814Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1

Area under the serum concentration-time curve (AUC) from time zero to the last sampling time point at which the concentration is at or above lower limit of quantification (LLOQ).

Part A: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1

Area under the serum concentration-time curve from time zero to infinity (AUC0-inf). AUC0-inf calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf.

Part B: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1

Area under the serum concentration-time curve from time zero to infinity (AUC0-inf). AUC0-infcalculated as AUC0-t + AUCextra.

Part A: Single Dose: Apparent Terminal Half-life (t1/2) of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15

T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve.

Part A: Multiple Doses: Apparent Terminal Half-life (t1/2) of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15

T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve.

Part B: Single Dose: Apparent Terminal Half-life (t1/2) of M3814Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1;Pre-dose, 2, 4 and 6 hours post-dose on Day 10

T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve.

Part B: Multiple Dose: Apparent Terminal Half-life (t1/2) of M3814Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1;Pre-dose, 2, 4 and 6 hours post-dose on Day 10

T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve.

Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1

The apparent volume of distribution during the terminal phase following extravascular administration, based on the fraction of dose absorbed. Vz/f = Dose/(AUC0-inf multiplied by Lambda z).

Part B: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M3814Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1

The apparent volume of distribution during the terminal phase following extravascular administration, based on the fraction of dose absorbed. Vz/f = Dose/(AUC0-inf multiplied by Lambda z).

Part A: Apparent Clearance (CL/f) of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

Part B: Apparent Clearance (CL/f) of M3814Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

Part A: Terminal Elimination Rate Constant (Lambda z) of M3814Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1

Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.

Part B: Terminal Elimination Rate Constant (Lambda z) of M3814Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1

Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.

Part A: Number of Participants With Positive Antidrug Antibody (ADA)Time from first study intervention up to long term safety follow-up period (Up to 516 Days)

Blood samples were analyzed by a validated homogenous bridging electrochemiluminescence assay to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported.

Part B: Number of Participants With Positive Antidrug Antibody (ADA)Time from first study intervention up to long term safety follow-up period (Up to 513 Days)

Blood samples were analyzed by a validated homogenous bridging electrochemiluminescence assay to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported.

Part FE: Number of Participants With Positive Antidrug Antibody (ADA)Part FE: From the first study intervention to 508 days

Serum samples were analyzed by a validated assay method to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported.

Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)Time from first study intervention up to long term safety follow-up period (Up to 516 Days)

Confirmed BOR was defined as the percentage of participants who achieved confirmed complete responses (CR) or partial response (PR), according to RECIST version 1.1 assessed by the Investigator.CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Confirmed CR=as at least two determinations of CR at least 4 weeks apart with no PD. Confirmed PR=as at least 2 determinations of PR or better (PR followed by PR or PR followed by CR), at least 4 weeks apart (not qualifying for a CR) with no PD in between. Percentage of Participants with confirmed BOR were reported.

Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)Time from first study intervention up to long term safety follow-up period (Up to 513 Days)

Confirmed BOR was defined as the percentage of participants who achieved confirmed complete responses (CR) or partial response (PR), according to RECIST version 1.1 assessed by the Investigator.CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Confirmed CR=as at least two determinations of CR at least 4 weeks apart with no PD. Confirmed PR=as at least 2 determinations of PR or better (PR followed by PR or PR followed by CR), at least 4 weeks apart (not qualifying for a CR) with no PD in between. Percentage of Participants with confirmed BOR were reported.

Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)Time from first study intervention up to long term safety follow-up period (Up to 404 Days)

Confirmed BOR was defined as the percentage of participants who achieved confirmed complete responses (CR) or partial response (PR), according to RECIST version 1.1 assessed by the Investigator.CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Confirmed CR=as at least two determinations of CR at least 4 weeks apart with no PD. Confirmed PR=as at least 2 determinations of PR or better (PR followed by PR or PR followed by CR), at least 4 weeks apart (not qualifying for a CR) with no PD in between. Percentage of Participants with confirmed BOR were reported.

Part A: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by InvestigatorTime from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 516 Days

DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

Part B: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by InvestigatorTime from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 513 Days

DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

Part FE: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by InvestigatorTime from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 44 Weeks

DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

Part A: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by InvestigatorTime from first study intervention up to long term safety follow-up period (Up to 516 Days)

Progression-Free Survival was calculated as the time from the start of any study intervention to the date of first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. The PFS was analyzed by using the Kaplan-Meier method.

Part B: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by InvestigatorTime from first study intervention up to long term safety follow-up period (Up to 513 Days)

Progression-Free Survival was calculated as the time from the start of any study intervention to the date of first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. The PFS was analyzed by using the Kaplan-Meier method.

Part FE: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by InvestigatorTime from first study intervention up to long term safety follow-up period (Up to 404 Days)

Progression-Free Survival was calculated as the time from the start of any study intervention to the date of first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. The PFS was analyzed by using the Kaplan-Meier method.

Part A: Overall SurvivalTime from first study intervention up to long term safety follow-up period (Up to 1359 Days)

Overall survival was defined as the time from treatment start to the date of death, regardless of the actual cause of the participant's death. The overall survival was analyzed by using the Kaplan-Meier method. Median, is estimated by Kaplan-Meier method which stands for the time that half of the participants are expected to be alive. Depending on the observed number of deaths, time of censoring for each participant, median survival time may not be reached or estimated (few deaths will lead the KM curve never crosses 50% survival line), hence median was not calculable for Part A: M3814 250 mg BID + Avelumab 800 mg Q2W arm. Participants that are still alive at the time of analysis will be censored and counted into the analysis.

Part B: Overall SurvivalTime from first study intervention up to long term safety follow-up period (Up to 1359 Days)

Overall survival was defined as the time from treatment start to the date of death, regardless of the actual cause of the participant's death. The overall survival was analyzed by using the Kaplan-Meier method. Median, is estimated by Kaplan-Meier method which stands for the time that half of the participants are expected to be alive. Depending on the observed number of deaths, time of censoring for each participant, median survival time may not be reached or estimated (few deaths will lead the KM curve never crosses 50% survival line), hence median was not calculable for Part B of the study. Participants that are still alive at the time of analysis will be censored and counted into the analysis.

Part FE: Overall SurvivalTime from first study intervention up to long term safety follow-up period (Up to 1359 Days)

Overall survival was defined as the time from treatment start to the date of death, regardless of the actual cause of the participant's death. The overall survival was analyzed by using the Kaplan-Meier method. Participants that are still alive at the time of analysis will be censored and counted into the analysis.

Part A: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1Time from first study intervention up to long term safety follow-up period (Up to 516 Days)

Tumor size is derived as the best percent change from baseline in target lesions (sum of longest diameter for non-nodal lesions and short axis for nodal lesions) at each time point.

Part B: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1Time from first study intervention up to long term safety follow-up period (Up to 513 Days)

Tumor size is derived as the best percent change from baseline in target lesions (sum of longest diameter for non-nodal lesions and short axis for nodal lesions) at each time point.

Part FE: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1Time from first study intervention up to long term safety follow-up period (Up to 404 Days)

Tumor size is derived as the best percent change from baseline in target lesions (sum of longest diameter for non-nodal lesions and short axis for nodal lesions) at each time point.

Part B: Number of Participants With Radiotherapy (RT)-Induced Toxicity According to NCI-CTCAE v 5.0Time from first study intervention up to long term safety follow-up period (Up to 512.4 Days)

Number of participants with radiotherapy-induced toxicities (mucositis and radiation dermatitis) were reported.

Trial Locations

Locations (8)

H. Lee Moffitt Cancer Center and Research Institute, Inc

🇺🇸

Tampa, Florida, United States

The University of Chicago Medical Center

🇺🇸

Chicago, Illinois, United States

Mount Sinai - PRIME (10707)

🇺🇸

Lake Success, New York, United States

University of Oklahoma Health Sciences Center - Stephenson Cancer Center

🇺🇸

Oklahoma City, Oklahoma, United States

UC Health Clinical Trials Office (10702)

🇺🇸

Cincinnati, Ohio, United States

Greenville Hospital System University Medical Center (ITOR)

🇺🇸

Greenville, South Carolina, United States

Vanderbilt-Ingram Cancer Center (8867)

🇺🇸

Nashville, Tennessee, United States

University of Pittsburgh Medical Center Health System

🇺🇸

Pittsburgh, Pennsylvania, United States

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