| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent ovarian cancer positive for MAGE-A4 in human leukocyte antigen (HLA)-A2+ subjects |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 anti-tumor activity of genetically modified autologous T-cells (ADP-A2M4CD8) as
monotherapy and in combination with nivolumab in HLA-A*02 positive subjects with MAGE-A4 positive recurrent ovarian cancer |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of genetically modified autologous T-cells (ADP-A2M4CD8) as monotherapy and in combination with nivolumab in HLA-A*02 positive subjects with MAGE-A4 positive recurrent ovarian cancer |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject (or legally authorized representative) has voluntarily agreed to participate by giving written informed consent in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and applicable local regulations.
2. Subject (or legally authorized representative) has agreed to abide by all protocol-required procedures including study-related assessments and management by the treating institution for the duration of the study, including LTFU.
3. Subject is ≥ 18 and ≤ 75 years of age at the time the Pre-Screening informed consent form (ICF) is signed.
4. Subject has histologically confirmed diagnosis of high-grade serous or high-grade endometrioid recurrent ovarian carcinoma, including primary peritoneal and fallopian tube carcinoma.
5. Subject has measurable disease according to RECIST v1.1 prior to lymphodepletion. Measurable disease is not required prior to leukapheresis.
6. Subject has the following disease-specific prior therapy requirements:
a. The initial therapy must have included at least 3 cycles of a prior platinum and taxane based chemotherapy regimen for primary disease, possibly including intraperitoneal therapy, consolidation, or extended therapy (maintenance/consolidation).
b. Subjects may receive up to 4 prior regimens of combination or single agent systemic treatment for recurrent or metastatic disease, which may include investigational therapies unless discussed and agreed upon with the Sponsor or designee.
c. Subjects who have received only 1 line of platinum based therapy must have progressed between 93 and 183 days of completing platinum based therapy as a
part of front line treatment of ovarian cancer. Subjects who have progressed within 92 days of completing platinum based therapy in front line treatment are excluded.
d. Subjects who have received 2 or more lines of platinum based therapy must have progressed during or within 183 days of completing the latest platinum based therapy for treatment of recurrent ovarian cancer. The number of days (platinumfree interval) should be calculated from the date of the last administered dose of platinum therapy to the date of documentation of progression.
e. Subjects with a known BRCA mutation (germ line or somatic) must have received a poly adenosine diphosphate-ribose polymerase (PARP).
f. Subjects must have received bevacizumab.
7. Positive for HLA-A*02:01, HLA-A*02:02, HLA-A*02:03, or HLA-A*02:06 allele as determined by Adaptimmune-designated central laboratory testing. HLA-A*02 alleles having the same protein sequence in the peptide binding domains (P group) will also be included. Other HLA-A*02 alleles may be eligible after adjudication with the Sponsor.
8. MAGE-A4 expression, defined as ≥ 30% of tumor cells that are ≥ 2+ by IHC, should be documented at the pre-screening period based on either an archival specimen or a fresh biopsy. All samples must have been pathologically reviewed by an Adaptimmune designated central laboratory confirming expression.
9. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
10. Subject has left ventricular ejection fraction (LVEF) of ≥ 50% or the institutional lower limit of normal range, whichever is lower.
11. Subject is fit for leukapheresis, and adequate venous access can be established for the cell collection.
12. Subjects of childbearing potential must have a negative urine or serum pregnancy test AND must agree to use a highly effective method of contraception starting at the first
dose of chemotherapy and continue for at least 12 months or for 4 months after the gene-modified cells are no longer detected in the blood, or 6 months after the last dose of nivolumab, whichever is longer. Subjects of childbearing potential must also agree to refrain from egg donation, storage, or banking during these same time periods. |
|
| E.4 | Principal exclusion criteria |
A subject meeting any of the following criteria is not eligible for participation in the study:
1. Positive for HLA-A*02:05 in either allele as determined by Adaptimmune-designated central laboratory. HLA-A*02 alleles having the same protein sequence as HLA-A*02:05 in the peptide binding domains (P groups) will also be excluded. Other alleles may be exclusionary after adjudication with the Sponsor.
2. Subject has received or plans to receive the following therapy/treatment prior to leukapheresis or lymphodepleting chemotherapy, unless stopped according to the washout requirements:
Note: The washout periods are provided as a guideline in the table below. Minor modifications to washout periods, if assessed as not clinically significant by the site study Investigator or designee, may be acceptable after discussing with the Sponsor Study Physician.
(for full details please refer to section 5.3 of the study protocol (Exclusion Criteria 2. )
3. Toxicity from previous anti-cancer therapy that has not recovered to Grade ≤ 1 or baseline prior to enrollment (except for nonclinically significant toxicities, e.g., alopecia and vitiligo). Subjects with Grade 2 toxicities that are deemed stable or irreversible (e.g., peripheral neuropathy) can be enrolled.
4. Subject has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cyclophosphamide, or other agents used in the study.
5. Subject has an active autoimmune or immune-mediated disease that has not yet resolved. Subjects with immune-mediated AEs secondary to treatment with immunotherapy that resolve to Grade ≤ 1 off steroids are permitted. Subjects with hypothyroidism, type I diabetes, adrenal insufficiency, or pituitary insufficiency that are stable on replacement therapy are eligible. Subjects with disorders such as asthma, vitiligo, psoriasis, or atopic dermatitis that are well controlled without requiring systemic immunosuppression are also eligible. Other stable immune conditions that do not require prednisone > 20 mg/day (or its equivalent for other corticosteroid agents) may be acceptable with the agreement of the Sponsor.
6. Subject had major surgery within 4 weeks prior to lymphodepletion; subjects should have been fully recovere from any surgical-related toxicities. Surgical-related toxicities which are not clinically significant per Investigator assessment may be acceptable after discussion and agreement with Study Physician.
7. Leptomeningeal disease, carcinomatous meningitis, or symptomatic central nervous system (CNS) metastases. Subjects with prior history of symptomatic CNS metastases must have received treatment (i.e., SRS, WBRT, or surgery) and be neurologically stable for at least 1 month, not requiring anti-seizure medications, and off of steroids for at least 14 days prior to leukapheresis and lymphodepletion. Subjects who have asymptomatic CNS metastases without associated edema, shift, or requirement for steroids or antiseizure medications are eligible. If such a subject receives SRS or WBRT, a minimum period of 2 weeks needs to lapse between the therapy and lymphodepletion. Prophylactic anti-seizure medication is allowed.
8. Subject has any other prior malignancy that is not considered by the Investigator to be in complete remission. Resectable squamous or basal cell carcinoma of the skin is acceptable. Prior malignancies that have been surgically resected and show no evidence of disease are acceptable.
9. Clinically significant cardiovascular disease including, but not limited to, any of the following:
a. Electrocardiogram (ECG) showing clinically significant abnormality at Screening
b. Uncontrolled clinically significant arrhythmias
c. Known family history or congenital history of prolonged QT syndrome or history of torsades de pointes
d. Uncontrolled hypertension despite optimal medical therapy
e. Acute coronary syndrome (angina or myocardial infarction) in the last 6 months
f. Clinically significant cardiac disease defined by congestive heart failure New York Heart Association Class 3 and 4
g. History of stroke, CNS bleeding, transient ischemic attack, or reversible ischemic neurological deficit within the last 6 months |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for efficacy is OR defined as complete response(CR) or partial response (PR) according to RECIST v1.1 by IRAC, from T-cell infusion until documented disease progression. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria of response are first met. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria of response are first met. |
|
| E.5.2 | Secondary end point(s) |
• AEs, including SAEs
• Incidence, severity, and duration of the adverse events of special interest (AESIs)
• Replication competent lentivirus (RCL)
• T-cell clonality and insertional oncogenesis (IO)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis will occur once all the subjects have either completed the Interventional Phase or completed up to 40 weeks follow-up post-T-cell infusion. At this time, all safety and secondary efficacy endpoints will be summarized to provide supportive evidence for the primary assessment. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| 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 | Yes |
| 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 | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Canada |
| United States |
| France |
| Spain |
| 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
|
The study will be considered complete once all subjects complete 15 years of follow-up, die, or withdraw early from the study, whichever comes first.
(chapter 4.6 of the study protocol, version 1.0) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 17 |
| 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 | 17 |
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