| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced/Metastatic EGFR-expressing Cancers |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced/Metastatic Cancers |
|
| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Dose Escalation Phase (Phase 1):
-To determine the maximum tolerated dose (MTD) and/or to select one or more recommended phase 2 doses (RP2Ds) of AFM24 in combination with atezolizumab.
Phase 2a:
-To evaluate the antitumor activity of AFM24 in combination with atezolizumab in terms of ORR. |
|
| E.2.2 | Secondary objectives of the trial |
Dose Escalation Phase (Phase 1):
- To assess the safety and tolerability of AFM24 in combination with atezolizumab
- To evaluate the preliminary antitumor activity of AFM24 in combination with atezolizumab in terms of objective response rate (ORR)
- To characterize the pharmacokinetic (PK) profile of AFM24 when AFM24 is given in combination with atezolizumab
- To assess the immunogenicity of AFM24 when AFM24 is given in combination with atezolizumab.
Phase 2a:
- To assess preliminary efficacy of AFM24 in combination with atezolizumab using additional measures of clinical benefit
- To assess the safety and tolerability of AFM24 in combination with atezolizumab
- To characterize the PK profile of AFM24 when AFM24 is given in combination with atezolizumab
- To assess the immunogenicity of AFM24 when AFM24 is given in combination with atezolizumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Voluntary provision and understanding of signed and dated, written informed consent prior to any mandatory study-specific procedures, sampling, or analysis.
2) Patients must be aged ≥18 years on the day of signing informed consent (or of an acceptable age according to local regulations, whichever is older).
3) Patients must have documented radiological progression during or after their latest therapy for all phases.
4) Patients have documented histologically or cytologically confirmed advanced or metastatic EGFR-positive (positive staining for EGFR in ≥1% of tumor cells determined by a locally validated immunohistochemistry assay) select cancer types, except for NSCLC
patients (cohorts EXP-1 and EXP-4), and meet the following criteria:
Dose Escalation Phase (Phase 1):
Dose Escalation Cohorts: Patients who meet the criteria specified for the expansion cohorts.
Expansion phase (Phase 2a):
-EXP-1: patients with advanced or metastatic, EGFR WT expressing NSCLC whose disease has progressed after having received ≥1 prior lines of therapy for advanced disease.
-EXP-2: patients with locally advanced, unresectable, or metastatic gastric or GEJ adenocarcinoma refractory to or, intolerant of, standard therapy.
-EXP-3: patients with advanced or metastatic hepatocellular carcinoma (other than fibrolamellar and sarcomatoid subtype; Barcelona Clinic Liver Cancer Stage C disease or Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy), hepatobiliary-, or pancreatic adenocarcinoma. Archived paraffin-embedded tumor tissue is acceptable for EGFR determination, otherwise a fresh tumor biopsy must be performed.
-EXP-4: patients 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.
5) ECOG Performance Status (PS) 0 or 1
6) Adequate organ function as determined by:
a. Hematological
i. Absolute neutrophil count (ANC) ≥1.5×10^9/L (1,500/mm3)
ii. Platelet count ≥75×10^9/L (75,000/mm3)
iii. Hemoglobin ≥ 9 g/dL.
b. Hepatic: Total bilirubin ≤1.5 × ULN or ≤3 × ULN in participants with Gilbert's syndrome, ALT and AST ≤2.5×ULN for patients without liver metastasis and ALT and AST ≤5×ULN for patients with liver metastasis or hepatocellular carcinoma (HCC). Albumin >3.0 g/dL. For HCC, Child-Pugh score <7 (Child-Pugh Class A) (APPENDIX H for details for the Child-Pugh Score classification).
c. Renal: Serum creatinine ≤1.5 × ULN OR Measured or calculated creatinine clearance ≥ 60 mL/min for patients with creatinine levels > 1.5 × institutional ULN.
d. INR or PT or aPTT ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy, in which case PT/aPTT must be within therapeutic range for intended use of anticoagulants.
Note: no growth factor or transfusion support within 7 days of testing allowed; and patients must be reassessed on or within 7 days of the first AFM24 infusion [i.e., Day -7] to remain eligible
7) Serum potassium, calcium, magnesium, and phosphate within normal limits or not worse than CTCAE v5.0 Grade 1 and asymptomatic.
8) Patients with inactive/asymptomatic carrier, chronic, or active hepatitis B virus (HBV) infection must meet the following criteria: HBV deoxyribonucleic acid (DNA) <500 IU/mL (or 2500 copies/mL) at screening.
Patients with cured hepatitis C virus (HCV) infection at screening can be enrolled.
9) Patients must have evaluable or measurable disease per RECIST v1.1 for the dose escalation phase (Phase 1). For the expansion phase (Phase 2a), patients must have measurable disease by RECIST v1.1.
10) Female patients of childbearing potential must have a negative urine or serum pregnancy test at Screening and prior to first AFM24 infusion (i.e., Day -7) to be eligible in this study.
11) 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 5 months after the last dose of study drug.
12) 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 5 months after the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
1) Currently receiving active treatment in any other clinical study, or administration of other investigational agent.
2) Treatment with any systemic anticancer therapy including investigational agent within 4 weeks of the first dose of the study drug, 6 weeks for mitomycin C or nitrosoureas, 2 weeks (or 5 half-lives whichever is longer) for using fluorouracil or small molecule targeted drugs, 2 weeks for using traditional Chinese medicine with anti-tumor indication. Anticancer therapies include cytotoxic chemotherapy, targeted inhibitors, and immunotherapies, but do not include hormonal therapy or radiotherapy for bone metastases >2 weeks prior to first AFM24 infusion (i.e.,Day-7).
3) Radiation therapy within 4 weeks before first dose of study drug (with the exception of limited palliative radiotherapy) or unresolved (CTCAE v5.0 >Grade 1) toxicity from previous radiotherapy (e.g. radiation dermatitis).
4) Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day -7 or anticipation of need for a major surgical procedure during the course of the study.
5) Has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or recombinant erythropoietin) within 14 days prior to first AFM24 infusion (i.e. D-7).
6) Patients with toxicities (because of prior anticancer therapy) which have not recovered to baseline or CTCAE v5.0 ≤ Grade 1, except for AEs not considered a likely safety risk (e.g. alopecia, neuropathy, specific laboratory abnormalities).
7) History of interstitial lung disease, or non-infectious pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening.
8) History of any other invasive malignancy, unless previously treated with curative intent and the patient has been disease free for 3 years or longer. Acceptable previous malignancies include completely removed in situ cervical intra-epithelial neoplasia, non-melanoma skin cancer, ductal carcinoma in situ, and early-stage prostate cancer that has been adequately treated.
9) Untreated or symptomatic central nervous system metastases including leptomeningeal disease or spinal cord compression.
10) One or more of the following cardiac criteria:
a. Unstable angina;
b. Myocardial infarction within 6 months prior to screening;
c. NYHA Class III and IV heart failure;
d. Corrected QT interval >470 msec obtained as the mean from 3 consecutive resting ECGs using the Fridericia’s formula;
e. Clinically important abnormalities in rhythm, conduction, or morphology of resting ECG;
f. Congenital long QT syndrome;
g. Uncontrolled hypertension despite maximum antihypertensive therapy.
11) Stroke or transient ischemic attack within 6 months prior to screening.
12) Has received a live vaccine administered within 28 days of planned treatment start (i.e. Day -7) or while participating in the study.
13) Diagnosis of immunodeficiency or active infection including known HBV, HCV, or HIV.
14) A known history or autoimmune disease requiring systemic immunosuppressive therapy; or any disease process requiring systemic immunosuppressive therapy (such as high-dose steroids defined as ≥10 mg prednisone or equivalent per day) within 4 weeks prior to the first
dose of AFM24.
Exceptions:
-Topical (≤20% of the skin surface area), ocular, intra-articular, intranasal, or inhalation corticosteroids with minimal systemic absorption
-Short Course (≤7 days) of corticosteroids prescribed prophylactically or for treatment of a non-autoimmune causes
-Physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency
15) Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with 14 days before the first dose of study treatment (i.e. Day -7) through 5 months after the last dose of study drug.
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 correspondingly.
17) Known hypersensitivity to monoclonal antibodies or any components used in the AFM24 or atezolizumab drug product preparations and any history of anaphylaxis; or uncontrolled asthma.
18) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic antibacterial, antifungal, or antiviral 2 weeks before the first dose of AFM24 infusion (on Day -7), decompensated cirrhosis, or psychiatric illness/social situations that would limit compliance with study requirements.
19) History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose Escalation Phase (Phase 1):
-Adverse events (AEs) to be assessed by the incidence and severity of dose-limiting toxicity (DLT) within the DLT observation period (Cycle 1)
Phase 2a
-ORR according to RECIST v1.1 determined by the Investigator assessment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Dose Escalation Phase (Phase 1):
≤28 days following the first dose of AFM24 in combination with
atezolizumab (Cycle 1).
Phase 2a:
For screening, radiographic tumor assessment is allowed up to 28 days prior to first
dose of AFM24 on Day -7.
CT or MRI will be done at Screening and during the last week of Cycle 2, 4, 6, 8, 10, 12 and every 3 cycles thereafter. |
|
| E.5.2 | Secondary end point(s) |
Dose Escalation Phase (Phase 1):
- Incidence of patients with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)
- ORR using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 determined by Investigator assessment
- PK parameters of AFM24: Cmax, Tmax, Cmin and AUCtau
- Frequency of patients developing anti-drug antibodies (ADAs) against AFM24
Phase 2a:
- Progression-free survival (PFS) according to RECIST v1.1 by Investigator assessment
- Duration of response (DOR) according to RECIST v1.1 by Investigator assessment
- Clinical benefit rate (CBR) according to RECIST v1.1 by Investigator assessment
- Disease control rate (DCR) according to RECIST v1.1 by Investigator
assessment
- Incidence of patients with TEAEs and SAEs
- PK parameters of AFM24: Cmax, Tmax, Cmin, and AUCtau
- Frequency of patients developing ADAs against AFM24 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As per the Protocol Schedule of assessments (Tables 7- 14) |
|
| 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 | Yes |
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Assessment of the safety, tolerability, PK, and efficacy of the combination AFM24 plus Atezolizumab |
|
| 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.8.3 |
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 | 12 |
| 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 Kingdom |
| United States |
| Poland |
| Spain |
|
| 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
|
| The study will be terminated as soon as the last patient ending treatment has completed the first long-term follow-up interval. |
|
| 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 | 17 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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