A Phase 1/2a study of AFM24 and Atezolizumab in patients with advanced and metastatic cancers

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Affimed GmbH, Affimed GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Nov 2021 → 11 Jun 2025

Decision date (initial)

2024-05-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Affimed GmbH

External identifiers

EU CT number

2024-511999-32-00

EudraCT number

2021-000707-20

ClinicalTrials.gov

NCT05109442

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Dose response, Pharmacokinetic, Pharmacodynamic

Dose Escalation Phase (Phase 1):
-To determine the MTD and/or to select one or more RP2Ds of AFM24 in combination with atezolizumab.
Phase 2a:
-To evaluate the antitumor activity of AFM24 in combination with other study drugs in terms of ORR.

Secondary objectives 2

1. 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 ORR. - 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.
2. Phase 2a: - To assess preliminary efficacy of AFM24 in combination with other study drugs using additional measures of clinical benefit. - To assess the safety and tolerability of AFM24 in combination with other study drugs - To characterize the PK profile of AFM24 when AFM24 is given in combination with other study drugs - To assess the immunogenicity of AFM24 when AFM24 is given in combination with other study drugs.

Conditions and MedDRA coding

Advanced/Metastatic EGFR-expressing Cancers

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Voluntary provision and understanding of signed and dated, written informed consent prior to any mandatory study-specific procedures, sampling, or analysis.
2. 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. 3. Patients must have documented radiological progression during or after their latest therapy for all phases.
4. 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 (for EXP-1, EXP-4, EXP-5, EXP-6, and the Dose Optimization cohorts; it should be provided if available), 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. -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 tyrosine kinase inhibitor (TKI) approved for EGFR mutated NSCLC, such as gefitinib, erlotinib, afatinib, dacomitinib or osimertinib. -EXP-5: 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-6: Patients with advanced or metastatic, EGFR WT expressing NSCLC whose disease has progressed after having received ≥1 prior lines of therapy for advanced disease. -Dose Optimization Cohort: Patients with advanced or metastatic, EGFR WT expressing NSCLC whose disease has progressed after having received ≥1 prior lines of therapy for advanced disease. Archived paraffin embedded tumor tissue is acceptable for EGFR determination, otherwise a fresh tumor biopsy must be performed.
5. 5. ECOG Performance Status (PS) 0 or 1.
6. 6. Adequate organ function as determined by: a. Hematological i. Absolute neutrophil count (ANC) ≥1.5×109/L (1,500/mm3) ii. Platelet count ≥100×109/L (100,000/mm3) iii. Hemoglobin ≥ 9 g/dL. b. Hepatic: i. Total bilirubin ≤1.5 × ULN or ≤3 × ULN in participants with Gilbert's syndrome, ii. Alkaline phosphatase <400 U/L, iii. ALT and AST ≤2.5×ULN for patients without liver metastases and ALT and AST ≤5×ULN for patients with liver metastases or hepatocellular carcinoma (HCC). iv. Albumin >3.0 g/dL. v. For HCC, ChildPugh 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. Urinary protein is ≤1+ on dipstick or routine urinalysis. If urine dipstick or routine analysis indicates proteinuria ≥2+, a 24-hour urine must be collected and must demonstrate less than 1000 mg of protein. 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. Patients treated with Factor Xa inhibitors must be stable on treatment for at least 3 months and with no bleeding events in the last 4 weeks. 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. 7. Serum potassium, calcium, magnesium, and phosphate within normal limits or not worse than CTCAE v5.0 Grade 1 and asymptomatic.
8. 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. 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. 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. 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 6 months after the last dose of study drug.
12. 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.

Exclusion criteria 32

1. 1. Currently receiving active treatment in any other clinical study, or administration of other investigational agent.
2. 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.
3. 9. Untreated or symptomatic central nervous system metastases including leptomeningeal disease or spinal cord compression.
4. 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.
5. 20. Patients with metastatic involvement of the bowel that have partial occlusion or are at risk of partial or complete bowel occlusion.
6. 21. Patients with chronic obstructive pulmonary disease (COPD) must be well controlled – demonstrated by the pulmonary function tests with bronchodilator challenge.
7. 22. Patients with forced expiratory volume in the first one second (FEV1)/forced vital capacity (FVC) <60% of predicted value (i.e. severe obstruction) in pulmonary function tests.
8. 23. Patients with lactate dehydrogenase levels ≥600 U/L
9. 24. Patients with centrally localized bulky disease.
10. 11. Stroke or transient ischemic attack within 6 months prior to screening.
11. 12. Has received a live vaccine administered within 28 days of planned treatment start (i.e. Day -7) or while participating in the study.
12. 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.
13. 13. Diagnosis of immunodeficiency or active infection including known HBV, HCV, or HIV.
14. 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. 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 drug (i.e. Day -7) through 5 months after the last dose of study drug.
16. 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. 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. 25. Radiographic evidence of major blood vessel invasion or encasement by cancer or intra-tumor cavitation, or gross hemoptysis within the preceding 2 months.
19. 26. Patients receiving chronic nonsteroidal anti-inflammatory agents (NSAIDs) or antiplatelet therapy other than once daily aspirin.
20. 27. Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of AFM24.
21. 28. Significant bleeding disorders, vasculitis, or Grade 3/4 gastrointestinal bleeding within 3 months prior to first dose of AFM24.
22. 29. Gastrointestinal perforation and/or fistulae within 6 months prior to first dose of AFM24.
23. 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.
24. 30. Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (e.g., hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.
25. 31. Patients with Grade ≥3 superior vena cava syndrome, pericardial effusion, pleural effusion, or ascites. Grade ≤2 pleural effusion at least 14 days after drainage is allowed.
26. 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 antitumor 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).
27. 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).
28. 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.
29. 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).
30. 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).
31. 7. History of interstitial lung disease, or non-infectious pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening.
32. 32. Patients with Grade ≥2 peripheral neuropathy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Dose Escalation Phase (Phase 1): -AEs to be assessed by the incidence and severity of DLT within the DLT observation period (Cycle 1) Phase 2a -ORR according to RECIST v1.1 determined by Investigator assessment

Secondary endpoints 3

1. 1. Dose Escalation Phase (Phase 1): - Incidence of patients with TEAEs and SAEs - ORR using RECIST v1.1 determined by Investigator assessment - PK parameters of AFM24: Cmax, Tmax, Cmin and AUCtau - Frequency of patients developing ADAs against AFM24
2. 2.1 Phase 2a: - PFS according to RECIST v1.1 by Investigator assessment - DOR according to RECIST v1.1 by Investigator assessment - CBR according to RECIST v1.1 by Investigator assessment
3. 2.2 Phase 2a: - 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Affimed GmbH

Sponsor organisation

Affimed GmbH

Address

Gottlieb-Daimler-Strasse 2, Oststadt Oststadt

City

Mannheim

Postcode

68165

Country

Germany

Scientific contact point

Organisation

Affimed GmbH

Contact name

Clinical Trial Manager

Public contact point

Organisation

Affimed GmbH

Contact name

Clinical Trial Manager

Third parties 11

Affimed GmbH

Sponsor organisation

Affimed GmbH

Address

Gottlieb-Daimler-Strasse 2, Oststadt Oststadt

City

Mannheim

Postcode

68165

Country

Germany

Locations

2 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Layperson summary Annex V

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications