177Lu-PSMA (177Lu-PNT2002) in PSMA-Positive Adenoid Cystic Carcinoma

A Phase 2, Single-Arm, Multi-center Study of 177Lu-PSMA (177Lu-PNT2002) in Patients With PSMA-Positive Adenoid Cystic Carcinoma

This is a single arm trial with one Cohort for people with recurrent or metastatic adenoid cystic carcinoma that cannot be treated with surgery. 10 participants will be enrolled in Cohort 1 at Johns Hopkins and will undergo DCFPyL PET/CT and 177Lu-PSMA dosimetry imaging only (single tracer dose). A feasibility analysis of dosimetry will be performed after meeting the accrual goal of Cohort 1 to determine if the study will proceed into Cohort 2.

If Cohort 2 proceeds, based on the dosimetry analysis, the major requirements of the study are to undergo treatment with 177Lu-PNT2002, have bloodwork, physical exams, and imaging done at study-specific time points, and to answer questionnaires. Patients will be in the study for about two years after enrolling.

Malignant salivary gland tumors account for approximately 3% to 5% of all head and neck cancers with approximately 0.4 to 2.6 cases per 100,000 people. Most patients present in the sixth to seventh decade of life. Adenoid cystic carcinoma (ACC) accounts for about 10% of all tumors of the salivary glands, often arises from the minor and major salivary glands but can also involve lacrimal and ceruminous glands, as well as other sites in the head and neck (nasal and paranasal sinuses, trachea, and larynx). Anatomically, ACC originates from the intercalated duct region and proliferates in three distinct architectural patterns: tubular, cribriform, and solid.

In the setting of recurrent and metastatic (R/M) ACC, first-line options include single-agent vinorelbine or mitoxantrone, or cyclophosphamide plus doxorubicin plus cisplatin (CAP). Overall response rates (ORR) are usually less than 15%. There are no effective second line options. While epidermal growth factor receptor (EGFR) has been shown to be overexpressed in some ACC, none of the phase II clinical trials of single agent cetuximab, gefitinib, or lapatinib demonstrated an objective response. Many cases of ACC also express the c-kit protein, however, use of single agent imatinib in patients with c-kit expression confirmed by immunohistochemistry (IHC) failed to produce an objective response. Phase II single agent sunitinib exhibited no objective response. Median progression free survival (PFS) of these phase II trials ranged from 3.5 months to 7.2 months. Ultimately, most patients with R/M ACC die from cancer, highlighting the need for effective therapies.

The investigators aim to examine and analyze PSMA-PET uptake in ACC to establish whether it is correlated to absorbed tumor dose and objective response in Cohort 1 participants.

Inclusion Criteria:

• Histologic confirmation of ACC (primary or metastatic tumor). Central review not required but local pathology review required (at Johns Hopkins or Stanford).
• Patients must have recurrent or metastatic ACC with measurable disease per RECIST 1.1, not amenable to definitive surgery or radiotherapy.
• Patients must have at least 1 lesion positive on PSMA-PET, as defined by standard uptake value (SUV) ratio of tumor to liver greater than one.
• Patient can have any or no prior systemic therapies.
• At least 28 days must have elapsed between last anti-cancer treatment administration and the initiation of study treatment, or at least 5 half-lives of the prior systemic therapy must have elapsed (whichever is shorter).
• Patient must have resolution of all previous treatment related toxicities to CTCAE version 5.0 grade of ≤ 2.
• Patient must be ≥ 18 years of age.
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

For female patients with childbearing potential or male patients with partners of childbearing potential, agreement to use barrier contraceptive method (condom) and to continue its use for 6 months from receiving the last dose of 177Lu-PSMA. Female patients with childbearing potential will undergo a urine pregnancy test. Pregnant female participants are excluded.

• Patient must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Spinal cord compression or impending spinal cord compression.
• Suspected pulmonary and/or liver metastases (greater >10 mm in largest axis).
• Unable to lie flat during or tolerate PET/CT.
• Refusal to sign informed consent.
• Any medical comorbidities that might preclude safe participation in the study.

Additional inclusion criteria only relevant if Cohort 2 participants enrolled:

• Adequate bone marrow reserve and organ function as demonstrated by complete blood count and chemistry panel completed within the prior 28 days demonstrating:

  1. Platelet count of >100 x109/L
  2. White blood cell (WBC) count > 3,000/mL
  3. Neutrophil count of > 1,500/mL
  4. Hemoglobin ≥ 10 g/dL
  5. Estimated glomerular filtration rate (eGFR) > 50 mL/min based upon Chronic Kidney Disease- Epidemiology Collaboration (CKD-EPI) equation. Due to safety concerns relating to renal clearance and toxicity of 177Lu-PSMA, patients with estimated GFR between 50 - 60 mL/min will require a 99mTc-TPA GFR test and only patients with non-obstructive pathology will be included in the study.
  6. Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤5 x upper limit of normal (ULN), total bilirubin < 3 x ULN
  7. Total bilirubin < 3 x ULN (except if confirmed history of Gilbert's disease)
  8. Serum albumin > 30 g/L

Additional exclusion criteria only relevant if Cohort 2 participants enrolled:

• Inadequate bone marrow reserve and organ function as detailed in eligibility criteria.
• Patient is participating in a concurrent investigative treatment protocol involving radiotherapy, surgery, or systemic anti-cancer agents.
• Patient receiving any other investigational agents.