E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049280 |
E.1.2 | Term | Solid tumour |
E.1.2 | System Organ Class | 100000004864 |
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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 |
Part 1:
- Determination of the MTD and/or MRD of MCLA-128
- Evaluation of adverse events (AEs) and dose limiting toxicities (DLT)
Part 2 (Safety):
- To characterize the safety and tolerability of MCLA-128
Part 2 (Efficacy):
- Evaluation of anti-tumor response and CBR |
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E.2.2 | Secondary objectives of the trial |
Part 1:
- To characterize the safety and tolerability of MCLA-128
- PK profile of MCLA-128
- Immunogenicity of MCLA-128
- Evaluation of anti-tumor response and CBR
- Presence of biomarkers and pharmacodynamic (PD) responses to MCLA-128
Part 2:
- PK profile of MCLA-128
- Immunogenicity of MCLA-128
- Evaluation of anti-tumor activity and clinical benefit
- Presence of biomarkers and PD responses to MCLA-128 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
General Inclusion Criteria for Part 1 and Part 2
1. Age 18 years or older;
2. At least one measurable or evaluable disease according to RECIST v1.1;
3. Performance status of ECOG 0 or 1;
4. Estimated life expectancy of at least 12 weeks;
5. Toxicities incurred as a result of previous anti-cancer therapy resolved to ≤Grade 1 (as defined by NCI CTCAE v4.03), except for alopecia, lymphopenia assessed as non-clinically significant, Grade 2 sensory neurotoxicity;
6. At least a 4-week interval between the last received radiotherapy and the first scheduled day of dosing with MCLA-128 (with the exception of up to 1X8 Gy for pain palliation);
7. Complete recovery from major surgery (stable and <Grade 2 toxicity acceptable);
8. Laboratory values at Screening:
a. Absolute neutrophil count ≥1.5 x 10e9/L without colony stimulating factor support;
b. Platelets ≥100 x 10e9/L;
c. Hemoglobin ≥9 g/dL or ≥2.2 mmol/L (not transfusion dependent);
d. Total bilirubin <1.5 times the upper limit of normal (ULN) (unless due to Gilbert’s syndrome);
e. AST (SGOT) ≤2.5 x ULN; ALT (SGPT) ≤2.5 x ULN; ≤5 x ULN for patients with advanced solid tumors with liver metastases; patients with confirmed bony metastases will be permitted on study with isolated elevations in ALP <5 x ULN;
f. Serum creatinine ≤1.5 x ULN or estimated glomerular filtration rate (GFR) of >50 mL/min based on the Cockroft-Gault formula;
g. Normal coagulation (elevated INR, prothrombin time or APTT <1.3 x ULN acceptable);
h. Urine protein ≤ 2+ (as measured by dipstick);) or ≤100 mg/24 hours urine
9. Able to provide an archival tumor biopsy sample or provision of consent to obtain fresh sample at Screening;
10. Candidate patients with metastatic colorectal cancer, should have availability of a pathology report indicating mutational status of “KRAS, NRAS, PIK3CA and BRAF” or provision of consent to obtain fresh biopsy sample at Screening;
11. Negative pregnancy test results available as defined by urine or blood human chorionic gonadotropin (hCG) test during Screening and within 7 days of Cycle 1, Day 1 in women of childbearing potential (defined as women ≤50 years of age or history of amenorrhea for ≤12 months prior to study entry);
12. Sexually active male and female patients of childbearing potential must agree to use an effective method of birth control (e.g., barrier methods with spermicides, oral or parenteral contraceptives and/or intrauterine devices) during the entire duration of the study and for 6 months after final administration of MCLA-128. Note that sterility in female patients must be confirmed in the patients’ medical records and be defined as any of the following: surgical hysterectomy with bilateral oophorectomy, bilateral tubular ligation, natural menopause with last menses >1 year ago; radiation induced oophorectomy with last menses >1 year ago; chemotherapy induced menopause with 1 year interval since last menses;
13. Ability to give written, informed consent prior to any study-specific Screening procedures, with the understanding that the consent may be withdrawn by the patient at any time without prejudice;
14. Capable of understanding the mandated and optional protocol requirements, is willing and able to comply with the study protocol procedures and has signed the main informed consent document. For any optional biopsy sampling (tissue and/or blood) and long-term sample storage, additional consent is required.
Specific Inclusion Criterion for Part 1
14. Histologically-confirmed and documented advanced or metastatic epithelial tumors, relapsed or refractory to at least 2 prior regimens of available standard treatment(s), or for which no curative therapy is available and MCLA-128 is a reasonable treatment option. This includes, but is not limited to, patients with breast cancer, gastric cancer, colorectal cancer, lung cancer or pancreatic cancer.
Specific Inclusion Criteria for Part 2 (Group A)
15. Histologically-confirmed and documented advanced or metastatic breast cancer (mBC) which is relapsed or refractory to prior available standard therapies including trastuzumab-containing regimens (prior treatment with other approved or investigational anti-HER2 or anti-HER3 agents is allowed);
16. At least 2 prior treatments for metastatic disease;
17. Confirmed HER2 amplification based on historical pathology report prior to commencing Screening assessments.
Specific Inclusion Criteria for Part 2 (Group B)
18. Histologically-confirmed and documented advanced or metastatic colorectal cancer (mCRC) which is relapsed or refractory to at least 2 prior regimens of available standard treatments for metastatic CRC, including one anti-EGFR treatment (if RASWT);
19. Confirmed HER2 amplification based on historical pathology report prior to commencing Screening assessments. |
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E.4 | Principal exclusion criteria |
General Exclusion Criteria for Part 1 and Part 2
1. Pregnant or lactating;
2. Presence of an active infection or an unexplained fever greater than 38.5°C during Screening up to the first scheduled day of dosing. At the discretion of the Investigator, patients with tumor fever may be enrolled;
3. Known hypersensitivity to any of the components of MCLA-128 or history of severe hypersensitivity reactions to human or humanized monoclonal antibodies, including therapeutic antibodies;
4. Known HIV, Hepatitis B or Hepatitis C; patients who have previously been treated for Hepatitis C and have undetectable viral loads are eligible;
5. Documented symptomatic or uncontrolled intracranial or leptomeningeal metastases or primary intracerebral tumor(s);
6. Previous or concurrent malignancy (excluding non-basal cell carcinoma of skin or carcinoma in situ of the uterine cervix) unless the tumor was treated with curative intent more than 2 years prior to study entry;
7. Prior anti-tumor therapy including:
a. Approved anti-HER2 therapies and/or anti-EGFR approved therapies within 28 days prior to the first scheduled day of dosing with MCLA-128;
b. Investigational therapy administered within 28 days prior to the first scheduled day of dosing with MCLA-128. Dosing with MCLA-128 within 28 days of receiving investigational therapy is acceptable once a time interval equal to at least five half-lives of the investigational agent has passed;
c. Treatment with chemotherapy agents within 28 days prior to the first scheduled day of dosing with MCLA-128;
8. Presence of NYHA Class III or IV congestive heart failure or LVEF <50% or history of significant cardiac disease, unstable angina, congestive heart failure, myocardial infarction, or ventricular arrhythmia requiring medication;
9. Presence of any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate or participate in the study, or interfere with the interpretation of the results. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1:
- Determination of MTD/MRD and tolerability
- Number and nature (severity and seriousness) of ADRs including DLTs
Part 2:
Primary Safety End Point:
- Number and nature (severity and seriousness) of ADRs and tolerability
Primary Efficacy End Point:
- Proportion of patients in whom at completion of study treatment period, a CBR (PR + CR + SD) is observed, based on RECIST. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Tumor assessment at Screening (up to 28 days prior to Cyc 1 D1), Cyc 2 D21; Cyc 4 D21, Cyc 5 onwards - after every 4 cyc D21, FSV, LTF
- AEs recorded at Cyc 1 D1, D2 - 4, D8, D15; Cyc 2-4 D1, D8 D15, D21; Cyc 5 onwards D1, D15, D21; EOT; FSV |
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E.5.2 | Secondary end point(s) |
Part 1:
- Number and nature (severity and seriousness) of ADRs and tolerability
- PK profile of MCLA-128
- Immunogenicity of MCLA-128
- Proportion of patients in whom at completion of study treatment period, a CBR (PR + CR + SD) is observed, based on RECIST
- Presence of biomarkers and pharmacodynamic (PD) responses to MCLA-128
Part 2:
- PK profile of MCLA-128
- Immunogenicity of MCLA-128
- Proportion of patients in whom at completion of study treatment period, a CBR (PR + CR + SD) is observed, based on RECIST
- Presence of biomarkers and PD responses to MCLA-128 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PK assessed at Cyc 1 D1, D2 - 4, D8, D15; Cyc 2-4 D1
- Immunogenicity assessed at Cyc 1 D1; Cyc 2-4 D1; EOT; FSV
- Biomarker/PD: Biopsy assessed at Screening (up to 28 days prior to Cyc 1 D1), end of Cyc 2, EOT; Blood assessed at Cyc 1 D1 (pre-dose), end of Cyc 2, EOT
- Tumor assessment at Screening (up to 28 days prior to Cyc 1 D1), Cyc 2 D21; Cyc 4 D21, Cyc 5 onwards - after every 4 cyc D21, FSV, LTF
- AEs recorded at Cyc 1 D1, D2 - 4, D8, D15; Cyc 2-4 D1, D8 D15, D21; Cyc 5 onwards D1, D15, D21, EOT, FSV |
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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 | Yes |
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 | Yes |
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 | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Part 2 is parallel design, Part 1 is not |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |