The purpose of this trial is to evaluate changes in immune activity relative to baseline
following treatment with Toca 511 and Toca FC in patients with solid tumors (including
recurrent high grade glioma [rHGG]) or lymphoma. This is a multicenter, open-label study of
Toca 511 and Toca FC. Patients with advanced solid tumors or lymphoma, for whom curative
options are not available, will be enrolled into the study, subject to all entry criteria.
Tumors must be accessible to biopsy and/or resection. Patients will be qualified based on the
presence of specific molecular characteristics, documented by Foundation Medicine (or
equivalent) genomic profile report, and specific tumor types.
Toca 511 will be administered by IV injection followed by (1) intratumoral injection
following biopsy or (2) injection into the resection cavity wall following planned resection
in the case of rHGG or brain metastases. Toca FC will be administered orally in cycles of
Patients not undergoing resection of brain tumors will undergo 2 biopsies to allow assessment
of baseline and follow-up immune activity in the tumor. Changes in immune activity in
peripheral blood will be measured in all patients.
1. Patient has given written informed consent.
2. Patient is between 18 and 75 years of age, inclusive.
3. Patient has an advanced malignancy that has progressed or recurred following standard
therapy for advanced disease, and for which no curative therapies are available.
4. Patient has histologically confirmed (1) colorectal cancer, triple negative breast
cancer, pancreatic cancer, non-small cell lung cancer, head and neck cancer, ovarian
cancer, lymphoma, sarcoma, bladder cancer, or melanoma with defects in one or more of
the following genes: ABL2, ACVR1B, APC, ASXL1, ATM, ATR, BLM, BRCA1, BRCA2, CDK12,
CDKN1A, CDKN1B, CDKN2A, CHD4, CYLD, DICER1, DNMT3A, ERBB3, EZH2, FGFR2, FLT3, GATA3,
HGF, KDM6A, KDR, KEAP1, KIT, KMT2D, KRAS, MAGI2, MAP3K1, MED12, MET, MSH-2, MSH-6,
MYC, NA, NF1, NF2, NOTCH1, NOTCH2, NRAS, NSD1, PIK3C2B, PIK3CA, PIK3CB, PIK3R1, PTCH1,
PTPN11, RB1, RUNX1, SETD2, SMARCA4, SOX9, STAG2, TAF1, TBX3, TET2, TP53, XPO1; (2)
documented IDH1 mutated solid tumor (other than glioma); or (3) documented IDH1
mutated or MGMT promoter methylation positive glioblastoma multiforme (GBM) or
anaplastic astrocytoma. Note: Genetic abnormalities must be documented by Foundation
Medicine (or equivalent) genomic profile report.
5. Patient has an estimated life expectancy of at least 6 months.
6. Patient has adequate organ function, as indicated by the following laboratory values
- Bone marrow: hemoglobin ≥ 10 g/dL, platelet count ≥ 100,000/mm3, absolute
neutrophil count ≥ 1,500/ mm3, absolute lymphocyte count ≥ 500/ mm3.
- Liver: total bilirubin ≤ 1.5 x the upper limit of normal (ULN; unless known
Gilbert's syndrome); alanine aminotransferase ≤ 2.5 x ULN (≤ 5.0 x ULN in
patients with liver metastases).
- Kidney: estimated glomerular filtration rate (Cockcroft-Gault) ≥ 50 mL/min.
7. Women of childbearing potential (defined as not postmenopausal [ie, ≥ 12 months of
non-therapy-induced amenorrhea] or not surgically sterile) must have a negative serum
pregnancy test within 21 days prior to initiation of Toca 511, and be willing to use
an effective means of contraception in addition to barrier methods (condoms).
8. Patient and partner are willing to use condoms for 12 months after receiving Toca 511
or until there is no evidence of the virus in his/her blood, whichever is longer.
9. Patients with solid tumors or lymphoma must have 1 or more tumors accessible to biopsy
or resection, including biopsy allowing multiple cores from at least 1 lesion (fine
needle aspiration is excluded), incisional or excisional biopsy, and/or resection.
Note: Patients with resectable brain metastases must be undergoing planned resection.
Patients with rHGG must be undergoing planned subtotal or gross total resection.
10. Patient has a tumor amenable to injection of Toca 511 (ie, ≥ 2 cm and not close to or
invading major vessels).
11. Patient has an ECOG Performance Status score of 0 or 1 (solid tumors) or KPS score ≥
12. Patient has measurable disease by RECIST version 1.1 (solid tumors) or Lugano
(lymphoma) criteria or evaluable or measureable disease by Macdonald criteria (rHGG).
13. Patients with GBM or anaplastic astrocytoma must be at first or second recurrence
(including this recurrence) or have progressed following initial definitive multimodal
therapy with surgery, temozolomide, and radiation (confirmed by diagnostic biopsy with
local pathology review or contrast-enhanced magnetic resonance imaging [MRI]). If
first recurrence is documented by MRI, an interval of at least 12 weeks after the end
of prior radiation therapy is required, unless there is either histopathologic
confirmation of recurrent tumor or new enhancement on MRI outside the radiotherapy
1. Patient has a history of other malignancy, unless the patient has been disease free
for at least 5 years. Adequately treated basal cell carcinoma or squamous cell skin
cancer is acceptable regardless of time, as well as localized prostate carcinoma or
cervical carcinoma in situ, after curative treatment.
2. Patient has or had any active infection requiring antibiotic, antifungal, or antiviral
therapy within the 2 weeks prior to administration of Toca 511.
3. Patient received chemotherapy within 2 weeks prior to initiation of treatment with
Toca 511 (6 weeks for nitrosoureas).
4. Patient received investigational treatment within 2 weeks or immunotherapy or antibody
therapy within 28 days prior to initiation of treatment with Toca 511, and/or has not
recovered from toxicities associated with such treatment.
5. For patients with rHGG, the patient intends to undergo treatment with the Gliadel®
wafer at the time of planned resection (ie, on-study surgery) or has received the
Gliadel wafer < 30 days from the date of planned resection.
6. Patient has any bleeding diathesis, or must take anticoagulants or antiplatelet
agents, including nonsteroidal anti inflammatory drugs, that cannot be stopped for
biopsy or surgery.
7. Patient has severe pulmonary, cardiac, or other systemic disease, specifically:
- New York Heart Association > Class II congestive heart failure that is not
controlled on standard therapy within 6 months prior to initiation of treatment
with Toca 511.
- Uncontrolled or significant cardiovascular disease, clinically significant
ventricular arrhythmia (such as ventricular tachycardia, ventricular
fibrillation, or Torsades de pointes), clinically significant pulmonary disease
(such as ≥ Grade 2 dyspnea, according to CTCAE 4.03).
- Any other disease, either metabolic or psychological, that as per Investigator
assessment may affect the patient's compliance or place the patient at an
increased risk of potential treatment complications.
8. Patient has a history of allergy or intolerance to flucytosine.
9. Patient has a condition that would prevent him or her from being able to swallow Toca
FC tablets or absorb flucytosine.
10. Patient is human immunodeficiency virus seropositive.
11. Patient is breast feeding.
12. Patient has previously participated in the Toca 5 trial (Tg 511-15-01).