| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced solid malignancies in patients whose disease has progressed after treatment with previous anticancer therapies. |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10048683 |
| E.1.2 | Term | Advanced cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
PHASE 1:
Determine the maximum tolerated dose (MTD), select a recommended phase 2 dose (RP2D), and investigate the safety and tolerability of AFM24 in patients with advanced solid malignancies.
PHASE 2a:
Assess the preliminary anti-tumor efficacy of AFM24, using tumor response criteria as defined by local RECIST v1.1 |
|
| E.2.2 | Secondary objectives of the trial |
PHASE 1:
Characterize the pharmacokinetics (PK) of AFM24 administered intravenously (i.v.); Characterize the immunogenicity of AFM24; and assess the preliminary anti-tumor efficacy of AFM24, using tumor response criteria as defined by: Local Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Local immune-related RECIST (iRECIST), Central RECIST v1.1, Central iRECIST
PHASE 2a:
Characterize the safety and tolerability of AFM24, including both acute and chronic toxicities; Characterize the PK of AFM24 administered i.v.; Characterize the immunogenicity of AFM24; and Assess the preliminary anti-tumor efficacy of AFM24, using tumor response criteria as defined by: Local iRECIST; Central RECIST v1.1; and Central iRECIST |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Patients with histologically or cytologically confirmed advanced or metastatic solid malignancies that are known to express EGFR, or in which EGFR is thought to be a relevant therapeutic target, including but not limited to: colorectal, lung, gastric, esophageal, pancreatic, head and neck, breast, ovarian, cervical, urothelial, and renal cancers, and glioblastoma multiforme
2) Patients must have been previously treated with one or more lines of anticancer therapy and have documented disease progression during or after their most recent line of anticancer therapy. In addition, either there is no further SOC therapy for the patient or the remaining SOC therapies are deemed not appropriate for the patient by the Investigator
3) Voluntary provision and understanding of signed and dated, written informed consent prior to any mandatory study-specific procedures, sampling, or analysis
4) Male or female aged ≥18 years on the day of signing informed consent
5) Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) 0 or 1 ≤7 days before first AFM24 infusion
6) Adequate organ function within 14 days before first AFM24 infusion, as defined as in the protocol. Patients must also be assessed as meeting these criteria on or within 7 days of the first AFM24 infusion to remain eligible
7) Serum potassium, calcium, magnesium and phosphorus within normal limits. If values are low on the initial screening assessment, supplements may be given and values repeated to confirm within normal limits
8) Patients must have at least one tumor site that is accessible to biopsy and that is considered by the Investigator to be low risk and of sufficient size to undergo a core biopsy procedure on at least 2 separate occasions
9) Phase 2a only: Patients must have measurable disease per RECIST v1.1 (i.e., at least 1 measurable lesion ≥10 mm by CT scan or MRI or ≥20 mm by chest X ray, malignant lymph nodes are considered measurable if short axis is ≥15 mm assessed by CT scan), with the last imaging performed within 28 days before Cycle (C) 1 Day (D) 1 (C1D1)
10) Patients in Phase 2a must have a disease history specific to their disease as listed below:
• Colorectal Cancer: Patients with metastatic colorectal carcinoma (mCRC) whose disease has progressed following prior treatment with oxaliplatin, irinotecan and a fluoropyrimidine for metastatic disease. Patients must have documentation of RAS mutational status. If RAS is wildtype, prior therapy must have included an approved anti-EGFR monoclonal antibody, i.e., either cetuximab or panitumumab, as a component. For patients with microsatellite instability-high or mismatch repair deficient mCRC prior lines of therapy must have included a checkpoint inhibitor if approved and available
• NSCLC without a targetable EGFR mutation: Patients with advanced or metastatic NSCLC whose disease has progressed after having received ≥2 prior lines of therapy for advanced disease, which must have included platinum-based therapy and an anti-PD-1/PD-L1 antibody. Patients must have documentation of NSCLC without a targetable EGFR mutation as assessed by genomic sequencing of tumor or circulating free tumor DNA. Patients with a targetable mutation other than EGFR must have received an approved targeted treatment if available. Patients with anaplastic lymphoma kinase (ALK)-positive tumor must have received an approved ALK inhibitor such as crizotinib, ceritinib, alectinib or lorlatinib. Patients with ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) rearrangement must have received an approved drug blocking the ROS1 protein such as crizotinib or entrectinib. It is recommended that patients with B-RAF V600E mutated NSCLC have received dabrafenib plus trametinib, if approved and available
• NSCLC with a targetable EGFR mutation: Patients with advanced or metastatic NSCLC harboring a targetable EGFR kinase domain mutation and whose disease has progressed after having received ≥1 prior lines of therapy for advanced disease including ≥1 prior tyrosine kinase inhibitor (TKI) approved for EGFR mutated NSCLC, such as gefitinib, erlotinib, afatinib, dacomitinib or osimertinib. Patients must have documentation of EGFR mutated NSCLC as assessed by an approved test using genomic sequencing of tumor or circulating free tumor DNA.
11) Female patients must have a negative urine or serum pregnancy test within 7 days prior to first dose of AFM24 if of childbearing potential or be of non-childbearing potential as defined in the protocol
12) Females of childbearing potential must agree to sexual abstinence or be willing to use a highly effective method of contraception for the course of the study from 14 days prior to the first dose of study drug through 120 days after the last dose of study drug
13) Males who have female partners of childbearing potential must agree to use a highly effective method of contraception starting with the first dose of study therapy through 120 days after the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
1) Currently participating in a study and receiving study therapy, or participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study treatment.
2) Treatment with systemic anticancer therapy within 4 weeks (6 weeks if therapy was mitomycin C and/or nitrosoureas), or within 5 half-lives of the agent if half-life is known and it is shorter, before first dose of study drug. Anticancer therapies include cytotoxic chemotherapy, targeted inhibitors, and immunotherapies, but do not include hormonal therapy or radiotherapy.
3) Radiation therapy within 2 weeks before first dose of study drug or unresolved (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0 >Grade 1) toxicity from previous radiotherapy (e.g., radiation dermatitis).
4) Major surgery within 4 weeks before first dose of study drug.
5) Patients with toxicities (as a result of prior anticancer therapy) which have not recovered to baseline or CTCAE v5.0 ≤ Grade 2, except for AEs not considered a likely safety risk (e.g., alopecia, specific laboratory abnormalities).
6) History of any other malignancy known to be active, with the exception of completely removed in situ cervical intra-epithelial neoplasia, non-melanoma skin cancer, ductal carcinoma in situ (DCIS), early stage prostate cancer that has been adequately treated, and other cancers from which the patient has been disease free for 3 years or longer.
7) One or more of the following cardiac criteria: Unstable angina; Myocardial infarction within 6 months prior to screening; New York Heart Association Class II to IV heart failure; Corrected QT interval (QTc) >470 msec obtained as the mean from 3 consecutive resting electrocardiograms (ECGs) using the Fridericia’s formula; Clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block or third-degree heart block); Congenital long QT syndrome; Uncontrolled hypertension (≥140/90 mmHg based on accurate measurement and average of ≥2 readings which are ≥5 minutes apart on ≥2 occasions).
8) Stroke or transient ischemic attack within 6 months prior to screening.
9) History of leptomeningeal disease or spinal cord compression.
10) Known brain metastases unless asymptomatic and not requiring steroids for at least 4 weeks prior to start of study treatment.
11) Patients with primary brain tumor who require high dose steroids (defined as≥30 mg prednisolone or equivalent per day) or who received high dose steroids within 4 weeks prior to first dose of study treatment.
12) Diagnosis of immunodeficiency or active infection including known hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
13) Active autoimmune disease that requires systemic treatment with steroids or other immunosuppressive agents, or patients who have received such agents within 1 months prior to first dose of study treatment. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
14) Patients who require systemic steroid treatment or any other immunosuppressive therapy, or patients who received such therapy within 4 weeks prior to the first dose of study treatment, with the exception of steroid allowance for primary brain tumor as outlined in exclusion criterion 11, or for physiologic replacement as outlined in exclusion criterion 13.
15) Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the Screening visit (females) or first dose of study treatment (males) through 120 days after the last dose of study treatment.
16) Patient’s unwillingness to comply with the protocol or inability to appreciate the nature, meaning, and consequences of the study and to formulate his/her own wishes accordingly.
17) Any medical, psychological, or social condition that would interfere with the patient’s participation in the study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PHASE 1:
The incidence of dose limiting toxicities (DLT) during DLT observation period.
PHASE 2a:
Overall response rate (CR+PR) assessed by local RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PHASE 1:
For cohorts 1&2, at least 2 patients, and for cohorts 3+, at least 3 patients, need to be evaluable for the dose-determining set. Patients must receive ≥80% of their assigned AFM24 dose in Cycle 1 and complete the 28-day DLT observation period or have had a DLT within the first cycle of treatment to be considered evaluable for DLT. Safety will be assessed by periodic vital signs, physical examinations, ECOG PS, 12-lead ECGs, clinical laboratory assessments, and monitoring of adverse events (AEs).
PHASE 2a:
Tumor assessment with CT and/or MRI will occur at Screening as well as during the last week of Cycles 2, 4, 6, 8, and every 3 cycles thereafter. Partial or complete response needs to be confirmed with repeated assessment at least 4 weeks after the initial assessment. |
|
| E.5.2 | Secondary end point(s) |
PHASE 1:
Serum PK parameters: area under the concentrationtime curve (AUC), Cmax, minimum plasma concentration (Cmin), clearance (CL), volume of distribution (Vd), volume of distribution at steady state (Vss), terminal t½
Measurement of anti-drug antibodies (ADA) before and throughout treatment with AFM24
Overall response rate (complete response [CR] + partial response [PR]), duration of response (DOR), and disease control rate (CR + PR + stable disease [SD]) assessed by Local RECIST v1.1; Local iRECIST; Central RECIST v1.1; and Central iRECIST. Progression-free survival (PFS), and overall survival (OS) measured by local and central assessments.
PHASE 2a:
AEs, SAEs, and changes between baseline and postbaseline laboratory parameters including ECGs, vital signs, and physical exams
PK parameters: AUC, Cmax, Cmin, CL, Vd, Vss, terminal t½
Measurement of ADA before and throughout treatment with AFM24
OR (CR + PR) assessed by Local iRECIST; Central RECIST v1.1; and Central iRECIST. DOR, and disease control rate (CR + PR + SD) assessed by Local RECIST v1.1; Local iRECIST; Central RECIST v1.1; and Central iRECIST.
PFS, OS measured by local and central assessments |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1 & 2a:
Safety will be assessed by periodic vital signs, physical examinations, ECOG PS, 12-lead ECGs, clinical laboratory assessments, and monitoring of adverse events (AEs).
Blood samples for PK assessments will be drawn during Cycle 1 on Days 1, 3, 7, 8, 15, 22, 24, and 28 as well as during Cycle 2 on Days 1, 8, 15, and 22, and during subsequent cycles on Day 1. PK Blood samples will also be drawn at the End of Treatment visit..
ADA will be measured on Days 1, 8, 15, and 22 in every cycle, and at the End of Treatment visit.
Disease response will be assessed by the Investigator, and imaging results will be sent for independent central review.
After the end of treatment patients will be followed for safety, DOR, PFS and OS until the end of the study
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Germany |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| 1 year after the last patient completes study treatment |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
Print
