| 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 one or more recommended phase 2 doses (RP2Ds), and investigate the safety and tolerability of AFM24 in patients with advanced or metastatic solid malignancies.
PHASE 2a:
Assess the preliminary antitumor efficacy of AFM24, by local Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. |
|
| E.2.2 | Secondary objectives of the trial |
PHASE 1:
Characterize the safety and tolerability of AFM24, including both acute and chronic toxicities; Characterize the pharmacokinetics (PK) of AFM24 administered intravenously (i.v.); Characterize the immunogenicity of AFM24; and; Assess the preliminary antitumor efficacy of AFM24.
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 antitumor efficacy of AFM24. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) For the dose escalation phase (Phase 1): histologically or cytologically confirmed advanced or metastatic solid malignancies that are known to
express EGFR. For the dose expansion phase (Phase 2a): histologically or cytologically confirmed advanced or metastatic EGFR malignancies. EGFR expression is defined as positive staining for EGFR in ≥1% of tumor cells, determined by a validated immunohistochemistry assay. Archived paraffin embedded tumor tissue is acceptable for EGFR determination – otherwise a fresh tumor biopsy must be performed. Local laboratory EGFR assessment is acceptable.
2) For dose escalation phase (Phase 1): Subjects must have been previously treated with 1 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 subject or the remaining SOC therapies are deemed not appropriate for the subject by the Investigator.
3) Subjects must have documented radiological progression during or after their latest therapy for all phases.
4) Voluntary provision and understanding of signed and dated, written informed consent prior to any mandatory study-specific procedures, sampling, or analysis
5) Male or female aged >=18 years on the day of signing informed consent (or of an acceptable age according to local regulations, whichever is older).
6) Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) 0 or 1
7) Adequate organ function assessed within 14 and within 7 days before first AFM24 infusion, as defined as in the protocol. Note: transfusions and hematopoietic growth factors to help meet eligibility are not allowed
8) Serum potassium, calcium, magnesium and phosphate within normal limits or not worse than CTCAE v5.0 Grade 1 and asymptomatic. If values
are low on the initial screening assessment, supplements may be given, if clinically appropriate, and values repeated to confirm within CTCAE
v5.0 Grade 1 limits.
9) For dose escalation phase (Phase 1): Subjects must have (mandatory) at least 1 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.
10) For dose expansion phase (Phase 2a) only: Subjects must have measurable disease per RECIST v1.1 (i.e., at least 1 measurable lesion >=10 mm by computed tomography [CT] scan or magnetic resonance imaging (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 1 Day 1 (C1D1).
11) Subjects in dose expansion phase (Phase 2a) must have histologically confirmed advanced or metastatic EGFR-positive malignancy for each expansion cohort, as listed below:
• Cohort A: Subjects with RAS-wildtype, microsatellite stable CRC whose disease has progressed after having received ≥2 prior lines of therapy, which must have included oxaliplatin, irinotecan, fluoropyrimidine. If available, prior therapy must also have included an anti-VEGF or, anti-
VEGFR and it's receptor (anti-VEGFR) therapy (eg, bevacizumab, aflibercept, or ramucirumab), and an anti-EGFR therapy (eg, cetuximab or panitumumab).
• Cohort B: Subjects with ccRCC whose disease has progressed after having received ≥1 prior line(s) of therapy, which must have included a
TKI (e.g., sunitinib, pazopanib), and a checkpoint inhibitor (e.g., pembrolizumab, avelumab, nivolumab).
• Cohort C: Subjects with advanced or metastatic NSCLC harboring a targetable EGFR kinase domain mutation and whose disease has progressed on or after having received ≥1 prior lines of therapy for advanced disease including ≥1 prior TKI approved for EGFR mutated NSCLC, such as gefitinib, erlotinib, afatinib, dacomitinib or osimertinib. Subjects who were treated with a 1st or 2nd generation TKI in 1st line and developed a documented T790M mutation must have received a TKI targeting this mutation such as osimertinib or lazertinib to be eligible. Subjects must have documentation of EGFR mutated NSCLC as assessed by an approved test using genomic sequencing of tumor or circulating free tumor DNA.
12) Female subjects 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
13) Females of childbearing potential must agree to sexual abstinence (defined in the protocol) 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
14) 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 drug 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 drug.
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] CTCAE v5.0 >Grade 1) toxicity from previous radiotherapy (e.g., radiation dermatitis).
4)Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks before first dose of study drug or anticipation of need of a major surgical procedure during the course of study. Note: Procedures that are considered to be minimally invasive (eg, peripherally inserted central catheters lines and/or port placements) will be exception.
5)Subjects 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 invasive malignancy, unless previously treated with curative intent and the subject has been disease free for 3 years or longer. Examples for acceptable previous malignancies include: completely removed in situ cervical intra-epithelial neoplasia, nonmelanoma skin cancer, ductal carcinoma in situ, and early-stage prostate cancer that has been adequately treated.
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 >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 (>= 150/100 mmHg based on accurate measurement and average of >=2 readings which are >=5 minutes apart on >=2 occasions) despite maximum antihypertensive therapy.
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 drug.
11)Subjects 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 drug.
12)Diagnosis of immunodeficiency or active infection including known hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). A negative confirmatory test within 3 months of treatment start does not have to be repeated during the screening period.
13)Active autoimmune disease that requires systemic treatment with steroids or other immunosuppressive agents, or subjects who have received such agents within 4 weeks prior to first dose of study drug.
Exceptions:
• Topical (≤20% of the skin surface area), ocular, intra-articular, intranasal, or inhalation corticosteroids with minimal systemic absorption
• A short course (≤7 days) of corticosteroids prescribed prophylactically (eg, for contrast dye allergy or antiemetic therapy) or for treatment of non-autoimmune causes (eg, delayed hypersensitivity reaction caused by contact allergen)
• Physiological replacement doses of corticosteroids for adrenal or pituitary insufficiency
14)Has received a live vaccine administered within 28 days of planned treatment start (C1D1) or while participating in the study. Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.
15)Subjects who require systemic steroid treatment or any other immunosuppressive therapy, or subjects who received such therapy within 4 weeks prior to the first dose of study drug, with the exceptions as outlined under exclusion criterion 13.
16)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 drug (males) through 120 days after the last dose of study drug.
17)Subject'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 correspondingly.
18)Any medical, psychological, or social condition that would interfere with the subject’s participation in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PHASE 1:
The incidence of 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 subjects, and for cohorts 3+, at least 3 subjects, need to be evaluable for the dose determining set. All subjects who start treatment need to complete the 28-day DLT observation period or experience a DLT before the SRC meeting and dose escalation decision (minimum of 2 subjects in cohorts 1/2 and 3 subjects in cohorts 3/4). Safety will be assessed by periodic vital signs, physical examinations, ECOG PS, 12-lead ECGs, clinical laboratory assessments, and monitoring of AEs.
PHASE 2a:
Tumor assessment with CT and/or MRI will occur at Screening and at timepoints specified in the protocol for weekly and every-2-week dose regimens. 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:
Incidence of subjects with TEAEs and SAEs
Serum PK parameters: AUCtau, Cmax, Tmax, Cmin.
Incidence of subjects who develop ADAs and neutralizing ADAs during treatment with AFM24 (by measurement of ADA before and throughout treatment with AFM24)
OR (CR + PR), DOR, and disease control (CR + PR + SD) assessed by Local RECIST v1.1.
PHASE 2a:
Incidence of subjects with TEAEs and SAEs
PK parameters: Cmax, Tmax, Cmin
Incidence of subjects who develop ADAs and neutralizing ADAs during treatment with AFM24 (by measurement of ADA before and throughout treatment with AFM24)
OR (CR + PR) assessed by Central RECIST v1.1; DOR, and disease control (CR + PR + SD) assessed by Local RECIST v1.1; Central RECIST v1.1.
PFS measured by local and central assessments
Overall Survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1 & 2a:
AEs will be periodically monitored.
Depending on the dosing regimen:
-PK assessments will be done on Days 1, 2, 3, 7, 8, 9, 15, 16, 22, 23, 24 and 28 (Cycle 1); Days 1, 2, 3, 7, 8, 9, 15, 16, 22, and 23 (Cycle 2); Day 1 (subsequent cycles) and at the End of Treatment (EoT) visit.
-ADA will be measured on Days 1, 8, 15, and 22 (Cycle 1); Days 1 and 15 (Cycle 2); Day 1 and 15 (subsequent cycles) and at the EoT visit.
Tumor assessment (CT/MRI): at Screening and in the last week of cycles 2, 4, 6, 8, and every 3 cycles thereafter (weekly dosing); every 8 weeks after baseline assessment (first 4 assessments), every 12 weeks thereafter (biweekly dosing).
After the EoT patients will be followed for safety, DOR, PFS and OS until the EoS. |
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| Korea, Republic of |
| United States |
| Spain |
| Germany |
| United Kingdom |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 7 |
| 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
