| Eligibility |
Inclusion Criteria:
- Subjects will be assessed for eligibility prior to leukapheresis AND prior to
lymphodepleting chemotherapy (unless otherwise noted) and must meet all specified
criteria for study participation.
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:
1. 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).
2. Subjects may receive up to 4 prior regimens of combination or single agent
systemic treatment for their disease, which may include investigational therapies
unless discussed and agreed upon with the Sponsor or designee. Note:
Neo-adjuvant/adjuvant treatment is considered as one line of treatment. Bridging
therapy is permitted and is not considered as a line of treatment.
3. 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.
4. 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
(platinum-free interval) should be calculated from the date of the last
administered dose of platinum therapy to the date of documentation of
progression.
5. Subjects with a known BRCA mutation (germ line or somatic) must have received a
poly adenosine diphosphate-ribose polymerase (PARP).
6. 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.
13. Subjects must have = 90% room air oxygen saturation test at rest at Screening (within
7 days of leukapheresis) and at Baseline.
14. Subject must have adequate organ function as indicated by the laboratory values in the
table below.
System Laboratory Value Hematological Absolute neutrophil count (ANC) = 1.5 × 109/L
(without granulocyte colony stimulating factor [G-CSF] support) Platelets = 100 × 109/L
(without transfusion support within 5 days prior to leukapheresis and lymphodepletion)
Hemoglobin (Hb) = 90 g/L (without transfusion support within 5 days prior to leukapheresis
and lymphodepletion) Coagulation Prothrombin time or international normalized ratio (INR) =
1.5 × upper limit of normal (ULN), unless receiving therapeutic anticoagulation Partial
thromboplastin time = 1.5 × ULN, unless receiving therapeutic anticoagulation Renal
Glomerular filtration rate (GFR) or creatinine clearance (CrCl) (estimated or calculated)1
= 50 mL/min /1.73 m2 or = 50 mL/min Hepatic Serum total bilirubin = 1.5 × ULN (unless
subject has documented Gilbert's Syndrome with direct bilirubin < 35% of total bilirubin)
Exception: Subjects with liver metastasis = 2.5 × ULN Alanine aminotransferase (ALT) /
Aspartate aminotransferase (AST) = 2.5 × ULN Albumin = 3 g/dL (Without albumin deficit
replacement within 7 days only prior to leukapheresis) Exception: Subjects with liver
metastasis = 5.0 × ULN
1 Renal function (GFR or CrCl) will be estimated or measured according to standard practice
at the treating institution. Renal function will be reassessed at Baseline using the same
methodology.
Note: Laboratory values that are slightly out of the laboratory test parameters, if
assessed as not clinically significant by the site study Investigator, may be acceptable
after discussion and review by the Sponsor Study Physician. This applies to screening
laboratory assessments and baseline laboratory assessments.
Exclusion Criteria:
1. Positive for HLA-A*02:05 in either allele as determined by Adaptimmune-designated
central laboratory testing. 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 to
leukapheresis or lymphodepleting chemotherapy, unless stopped according to the washout
requirements:
Cytotoxic chemotherapy Required Washout Prior to Leukapheresis 3 weeks Required
Washout Prior to Lymphodepletion: 3 weeks
Small molecules/tyrosine kinase inhibitors (TKIs), such as dabrafenib, trametinib,
vemurafenib, and cobimetinib Note: No washout period is required for compounds that do
not cause bone marrow suppression/lymphopenia or for epidermal growth factor receptor
and alkaline phosphatase/ ROS 1 inhibitors. Required Washout Prior to Leukapheresis 1
week Required Washout Prior to Lymphodepletion: 1 week
Immune therapy (including monoclonal antibody therapy, checkpoint inhibitors, and
biologics) other than anti-PD(L)1 Required Washout Prior to Leukapheresis 2 weeks
Required Washout Prior to Lymphodepletion: 2 weeks
Anti-PD(L)1 Required Washout Prior to Leukapheresis 2 weeks Required Washout Prior to
Lymphodepletion: 6 weeks
Experimental anti-cancer vaccine Required Washout Prior to Leukapheresis: N/A Required
Washout Prior to Lymphodepletion: Eight weeks in the absence of tumor response.
The subject should be excluded if their disease is responding to an experimental
vaccine given within 6 months.
Gene therapy using an integrating vector Subjects who have received a gene therapy
using any DNA-integrating vector other than a lentivirus (retrovirus, Adeno-associated
Virus (AAV), etc.) are excluded from this study. Use of previous gene therapy using a
lentiviral vector is permitted. If transduced T-cells represent < 1% of PBMCs (< 1500
copies of vectors/µg of PBMC DNA) at the time of screening. Eligibility testing must
be done by Adaptimmune's designated Contract Research Organization (CRO). Required
Washout Prior to Lymphodepletion: N/A
Corticosteroids or any other immunosuppressive therapy Note: Use of topical or inhaled
steroids is not an exclusion. See Section 6.5.1 for exceptions.
Required Washout Prior to Leukapheresis: 2 weeks Required Washout Prior to
Lymphodepletion 2 weeks
Anti-MAGE-A4 therapy Note: Fresh screening biopsy post-anti-MAGE-A4 therapy must be
obtained to confirm MAGE-A4 positivity by IHC. Required Washout Prior to
Leukapheresis: 2 weeks Required Washout Prior to Lymphodepletion: 2 weeks
Investigational treatment Required Washout Prior to Leukapheresis 2 weeks or 5
half-lives, whichever is shorter Required Washout Prior to Lymphodepletion: 2 weeks or
5 half-lives, whichever is shorter.
Radiation to vital organs (e.g., liver, kidney) Required Washout Prior to
Leukapheresis: N/A Required Washout Prior to Lymphodepletion: 4 weeks
Radiation to the pelvis Required Washout Prior to Leukapheresis: 4 weeks Required
Washout Prior to Lymphodepletion: 4 weeks
Whole brain radiotherapy (WBRT) or brain stereotactic radiosurgery (SRS) Required
Washout Prior to Leukapheresis N/A Required Washout Prior to Lymphodepletion: 2 weeks
Radiotherapy to the target lesions Required Washout Prior to Leukapheresis: N/A
Required Washout Prior to Lymphodepletion: 3 months prior to lymphodepleting
chemotherapy or a target lesion with progression post radiotherapy (Note: There is no
washout period for palliative radiation to non-target organs.)
PARP inhibitor Required Washout Prior to Leukapheresis: 1 week Required Washout Prior
to Lymphodepletion: 1 week
Antibody drug conjugates (such as mirvetuximab) Required Washout Prior to
Leukapheresis: 3 weeks Required Washout Prior to Lymphodepletion: 3 weeks Note:
Duration of any other anti-cancer therapies must be discussed and agreed upon with the
Sponsor Study Physician
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 biological 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 been
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 recovered from any surgical-related toxicities. Surgical-related
toxicities that are not clinically significant per Investigator assessment may be
acceptable after discussion and agreement with the 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, or off 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 anti-seizure 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:
1. Electrocardiogram (ECG) showing clinically significant abnormality at Screening
2. Uncontrolled clinically significant arrhythmias
3. Known family history or congenital history of prolonged QT syndrome or history of
torsade de pointes
4. Uncontrolled hypertension despite optimal medical therapy
5. Acute coronary syndrome (angina or myocardial infarction) in the last 6 months
6. Clinically significant cardiac disease defined by congestive heart failure New
York Heart Association Class 3 and 4
7. History of stroke, CNS bleeding, transient ischemic attack, or reversible
ischemic neurologic deficit within last 6 months
10. Uncontrolled intercurrent illness including, but not limited to, any of the following:
1. Ongoing or active systemic infection, or localized infection which may become
systemic due to leukapheresis procedure, e.g., catheter insertion will be
excluded. Subjects with urinary tract infections will be included only following
treatment with antibiotics.(For SARS-CoV 2 [COVID-19] infection, see Section
10.4.4.1)
2. Clinically significant pulmonary disease with any 1 pulmonary function parameter
< 60% predicted (forced expiratory volume first forced breath [FEV1], total lung
capacity [TLC], or diffusing capacity of lungs for carbon monoxide [DLCO]; note:
for patients with anemia, corrected DLCO could be used) assessed prior to
leukapheresis and within 2 months of the start of lymphodepleting chemotherapy
3. Requirement for oxygen support (due to cardiac or pulmonary disease)
4. Interstitial lung disease (pneumonitis) or history of pneumonectomy or chronic
obstructive pulmonary disease with = 1 exacerbation within 1 year prior to the
Screening Visit that required treatment with systemic corticosteroids or resulted
in hospitalization
5. Hospitalization for bowel obstruction in last 2 months
6. Hematosis or significant organ bleeding in last 2 months
7. Ascites or pleural effusion which requires repeated (2 within 4 weeks)
paracentesis or thoracentesis within last 2 months
8. Cardiac or pericardial tumor involvement (prior to lymphodepletion)
11. Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV),
hepatitis C virus (HCV), or human T cell leukemia virus (HTLV) as defined below.
Re-screening for infectious disease markers is not required at baseline (prior to
lymphodepletion) unless > 6 months has elapsed.
1. Positive serology for HIV
2. Active hepatitis B infection as demonstrated by test for hepatitis B surface
antigen. Subjects who are hepatitis B surface antigen negative but are hepatitis
B core antibody-positive must have undetectable hepatitis B DNA and receive
prophylaxis against viral reactivation. Prophylaxis should be initiated prior to
lymphodepleting therapy and continued for 6 months.
3. Active hepatitis C infection as demonstrated by hepatitis C ribonucleic acid
(RNA) test. Subjects who are HCV antibody-positive will be screened for HCV RNA
by any reverse transcription-polymerase chain reaction (RT PCR) or branched DNA
(bDNA) assay. If HCV antibody is positive, eligibility will be determined based
on a negative screening RNA value.
4. Positive serology for HTLV 1 or 2
12. Subject is pregnant or breastfeeding.
13. Subjects who have illicit drug or alcohol dependency within the past year.
14. In the opinion of the Investigator, subject will be unlikely to fully comply with
protocol requirements.
15. Intolerance to nivolumab includes severe allergic reaction to nivolumab or any
components (active or inactive) of nivolumab.
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