| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| cancer (malignant solid tumors) |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| 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 |
-To evaluate the safety/tolerability of intravenous M6620 administered:
Part A–multiple ascending doses (MAD) in comb with gem, and with
cis/gem in subjects with advanced solid tumors (aST)
Part B–MAD in comb with cis, and with cis/etp in subjects with aST
Part B2-MAD in comb with irino in subjects with aST
Part C1-with gem in subjects with advanced NSCLC with TP53 mutation,
with ATM loss of expression and without TP53 mutation and ATM loss of
expression
Part C2-with cis in subjects with advanced TNBC
Part C3-with cis /carboplatin in subjects with platinum-resistant
advanced SCLC
-To assess the ORR by RECIST 1.1 in:
Part C1-advanced NSCLC with TP53 mutation, with ATM loss of
expression and without TP53 mutation and ATM loss of expression to the
comb of M6620 and gem
Part C2-advanced TNBC who are basaloid subtype and BRCA1/BRCA2
germline wild-type to the combination of M6620 and cis
Part C3-Pt-resistant advanced SCLC to the combination of M6620 and cis
or carboplatin
|
|
| E.2.2 | Secondary objectives of the trial |
PART A + PART B + PART B2
-MTD of M6620 administered with cis, M6620 with cis/gem, M6620 with
gem, M6620 with cis/etp & M6620 with irino in advanced solid tumors
-Evaluate PK of M6620 with gem, or with cis / gem, M6620 with cis, or
M6620 with cis / etp and M6620 with irino in advanced solid tumors
-Response of advanced solid tumors to M6620 with gem & M6620 with
cis / gem, M6620 with cis and M6620 with cis / etp and M6620 with irino
by CT scan
-PK of etp with M6620 & cis (PART B)
PART C1
Assess PFS, RD, OS, CR, PR, SD &PK in subjects with advanced NSCLC
with TP53 mutation, with ATM loss of expression, &without TP53
mutation & ATM loss of expression, administered M6620 & gemcitabine
PART C2
To assess ORR, PFS, RD, OS, CR, PR, SD &PK in subjects with advanced TNBC, administered M6620 in combination with cisplatin
PART C3
To assess PFS, RD, OS, SD and PK in subjects with platinum-resistant
advanced SCLC, administered M6620 in combination with cisplatin or
carboplatin. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects who meet all of the following inclusion criteria will be eligible for this study:
1.Male and female subjects ≥18 years of age
2.Disease status
Parts A and B/B2: Histologically or cytologically confirmed advanced solid tumor that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective, or for whom regimens containing gemcitabine, cisplatin, and/or etoposide might be considered, and with measurable disease according to RECIST criteria (Version 1.1)
Part C1:
Pre-screening: subjects who are not current candidates for study drug treatment or do not elect to be candidates at this time, but may be candidates in the future:
a.Advanced (metastatic or locally-advanced unresectable and not eligible for definitive treatment, e.g., surgery/radiotherapy) histologically confirmed NSCLC
b.Available historical tumor specimen available for shipment to the sponsor as confirmed by the investigator unless otherwise agreed to by the sponsor or willing to provide a tumor biopsy (core) if the biopsy may be considered as part of standard clinical practice for the patient
c.Received or did not tolerate standard approved targeted therapy, if appropriate for tumor genotype (e.g., targeted therapies for ALK rearrangement or EGFR activating mutations)
Screening: subjects who are current candidates for study drug treatment:
a.Measurable disease according to RECIST criteria (Version 1.1)
b.Meet inclusion criteria a through c for Part C1 pre-screening.
Part C2:
a.Advanced (locally-advanced incurable or metastatic), histologically confirmed estrogen receptor, progesterone receptor, and HER2 negative breast cancer
b.Adequate available historical tumor specimen (core biopsy or surgical specimen; fine needle aspirate inadequate) available for shipment to the sponsor as confirmed by the investigator unless otherwise agreed to by the sponsor, or willing to provide a tumor biopsy (core) if the biopsy may be considered as part of standard clinical practice for the patient
c.Measurable disease according to RECIST criteria (Version 1.1)
Part C3:
a.Advanced (locally-advanced incurable or metastatic), histologically confirmed SCLC that is platinum-resistant, defined as disease progression during initial treatment with a platinum-based regimen or progression within 90 days of completion of platinum therapy. Subjects with platinum-resistant disease may receive a second-line non-platinum-based chemotherapy and subsequently be enrolled to this study. Subjects who received and are resistant to a second-line platinum-based chemotherapy, (i.e., progressing on or within 90 days of treatment with a platinum-based regimen) may also be enrolled into the study.
b. Adequate available historical tumor specimen if available (core biopsy or surgical specimen; fine needle aspirate inadequate) or willing to provide a tumor biopsy (core) if the biopsy may be considered as part of standard clinical practice for the patient. If a historical sample is unavailable, a subject may be enrolled at the discretion of the investigator and sponsor.
c. Measurable disease according to RECIST criteria (Version 1.1)
3.WHO performance status of 0 or 1
4.Life expectancy of ≥12 weeks
5.Hematological and biochemical indices within the ranges shown below at screening. No clinically significant change in these values must be confirmed on the first day of dosing, before study drug administration.
a.Hemoglobin: ≥8.0 g/dL
b.Absolute neutrophil count: ≥1.5 109/L
c.Platelet count: ≥100 109/L
d.Serum bilirubin: ≤1.5 upper limit of normal (ULN), unless the subject has known or suspected Gilbert’s syndrome
e.ALT and aspartate aminotransferase (AST): ≤2.5 (ULN) or ≤5 ULN in presence of liver metastases
f.Estimated glomerular filtration rate: Parts A and B: ≥50 mL/min or ≥60 mL/min for subjects who will receive a cisplatin containing regimen
Part C1: ≥50 mL/min
Parts C2 and C3: ≥60 mL/min (with cisplatin) and ≥40 mL/min (with carboplatin)
g.Prothrombin time: <1.5 ULN
h.In addition, there should not be other clinically-significant metabolic or hematologic abnormalities that are uncorrectable or that require on-going, recurrent pharmacologic management.
6.Sign and date an informed consent document. A separate pre-screening informed consent will be required for potential subjects who undergo pre-screening in Part C1.
7.Willing and able to comply with scheduled visits, treatment plan, lifestyle, laboratory tests, contraceptive guidelines, and other study procedures
|
|
| E.4 | Principal exclusion criteria |
1.Radiotherapy (except for palliative reasons) endocrine therapy, immunotherapy, or chemotherapy during the previous 4 weeks (6 weeks for nitrosoureas and Mitomycin C, and 4 weeks for investigational medicinal products) or less than 4 drug half-lives.
2.Prior chemotherapy
Parts A and B/B2:
•Greater than 6 cycles of prior treatment with cisplatin and/or carboplatin, unless discussed with and approved by Vertex medical monitor.
•Subjects with a known history of Grade 4 thrombocytopenia or Grade 4 neutropenia while receiving prior therapy, unless discussed with and approved by Vertex medical monitor.
Part C1:
a.Any cytotoxic chemotherapy beyond 1 line of platinum-based chemotherapy. One additional line of non-platinum based therapy in the advanced setting is allowed.
b.Any prior gemcitabine for the treatment of NSCLC in any setting within 6 months
Part C2:
a.Any prior platinum therapy in the adjuvant or neoadjuvant within 6 months of screening
b.Relapse within 3 months of completion of prior adjuvant or neoadjuvant chemotherapy
c.Any prior chemotherapy in the metastatic setting except a taxane and/or an anthracycline and 1 other non-platinium-based chemotherapy in the first- and second-line metastatic setting
Part C3:
a. Prior platinum-sensitive subjects, unless they progress on or within 90 days of completion of platinum-based regimen
b. There is no restriction on prior immunotherapy or targeted therapy in the metastatic setting unless combined together with a cytotoxic agent
c. During prior carboplatin therapy, requirement for dose reduction below AUC 5 mg.min/mL or discontinuation of carboplatin for toxicity or lack of tolerability. However, the subject would be eligible to receive cisplatin as long as otherwise meets criteria and is discussed with sponsor
3.Biomarkers
Part C1:
a. Subjects who are known to be TP53 wild-type, unless they are determined to have ATM loss of expression during screening or pre-screening or until all the planned subjects with TP53 mutation are enrolled as determined by the medical monitor
b. Subjects with unknown TP53 mutational status will be enrolled until the group of approximately 10 subjects without TP53 mutation or until all the planned subjects with TP53 mutation are enrolled as determined by the medical monitor
Part C2
a.Subjects with known BRCA1/BRCA2 germline mutations, either determined and documented prior to Screening, or determined during Screening. Subjects with unknown BRCA1/BRCA2 status may be enrolled.
b.Subjects who are documented to be non-basaloid subtype using molecular profiling assay (e.g. PAM50 assay) prior to Screening
c.Subjects with unknown BRCA1/BRCA2 or basaloid subtype status will be enrolled until the number of enrolled subjects is approximately 40. If approximately 40 subjects have been enrolled and a minimum of 30 subjects who are basaloid positive and BRCA1/BRCA2 germline wild-type have not been enrolled, the basaloid subtype and BRCA status assay will be required at Screening to exclude subjects who are basaloid negative or have BRCA1/BRCA2 germline mutations.
4.Unresolved toxicity of CTCAE Grade 2 or greater from previous anti-cancer therapy or radiotherapy, excluding:
a.Alopecia, anemia or leukopenia or other toxicities that in the opinion of the investigator and the sponsor should not exclude the subject
5.History of spinal cord compression or brain metastases. Any history of leptomeningeal metastases.
6.Female subjects who are already pregnant or lactating, or plan to become pregnant within 6 months of the last dose of study drug are excluded.
7.Male subjects with partners of child-bearing potential must agree to adhere to contraception guidelines in Section 12.7.5.
8.Major surgery ≤2 weeks before starting study drug, or incomplete recovery from a prior major surgical procedure.
9.Cardiac conditions as specified in the protocol.
10.Prior bone marrow transplant or extensive radiotherapy to greater than 15% of bone marrow*
11.Participation or plan of participation in another interventional clinical study while taking part in this Phase 1 study of M6620. Participation in an observational study would be acceptable.
12.Any other condition which in the investigator’s opinion would not make the subject a good candidate for the clinical study
13.Part C: Current malignancies other than malignancies of interest, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Subjects with prior non-NSCLC (Part C1) or non-TNBC (Part C2) malignancies that have been in remission for less than 3 years are excluded. For part C3, prior cancer that has been in remission for at least 1 year would not be excluded. Also, other malignancies that the PI deems to be not clinically relevant would not be excluded if agreed to with the sponsor.
14.Subject is directly involved with the conduct of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Parts A and B/B2:
Safety parameters, including AEs, clinical laboratory values (serum chemistry, hematology and urinalysis), vital signs, and ECG assessments
Part C1, C2, C3
-Safety parameters, including AEs, clinical laboratory values (serum chemistry, hematology, and urinalysis), vital signs, and ECG
-ORR (all subjects in Part C1)
-ORR for subjects in Part C2 who are basaloid subtype and BRCA1/BRCA2 germline wild-type
-ORR (all subjects in Part C3) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of treatment + 14 days (safety f/u visit) |
|
| E.5.2 | Secondary end point(s) |
PART A:
- MTD of M6620 administered in combination with cisplatin and
gemcitabine and in combination with gemcitabine
- PK parameters estimates of M6620 in combination with cisplatin and
gemcitabine and in combination with gemcitabine
- OR as evaluated by RECIST 1.1
Part B
- MTD of M6620 in combination with cisplatin and in combination with
cisplatin and etoposide
- PK parameter estimates of M6620 in combination with cisplatin and in
combination with cisplatin and etoposide
-PK parameter estimates of etoposide derived from plasma
concentration-time data after coadministration with M6620 and in the
absence of M6620
- OR as evaluated by RECIST 1.1
PART B2
-MTD of M6620 administered in combination with irinotecan
-PK parameter estimates of M6620 in combination with irinotecan
-OR as evaluated by RECIST 1.1
PARTS C1, C2, C3
ORR (all subjects in Part C2)
PFS
RD
OS
Clinical benefit (CR + PR + SD of 6 months or greater)
PK parameter estimates of M6620
- PK parameter estimates of M6620 in combination with cisplatin and in
combination with cisplatin and etoposide
-PK parameter estimates of etoposide derived from plasma
concentration-time data after coadministration with M6620 and in the
absence of M6620
- OR as evaluated by RECIST 1.1
PARTS C1, C2, C3
ORR (all subjects in Part C2)
PFS
RD
OS
Clinical benefit (CR + PR + SD of 6 months or greater)
PK parameter estimates of M6620 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of treatment + 8 weeks (last follow=up visit) |
|
| 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 | No |
| 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 | 6 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| 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 |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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