AlphaMedix™ (²¹²Pb-DOTAMTATE) is a radiotherapeutic drug indicated in subjects with
unresectable, metastatic somatostatin receptor (SSTR) positive neuroendocrine tumors (NETs).
Because 212Pb is an in vivo generator of alpha particles, it is particularly suitable for
SSTR therapy applications.
This drug addresses an unmet need in the field of peptide receptor radionuclide therapy
(PRRT) for NETs. Substitution of an alpha emitter (²¹²Pb) for the beta emitters currently
being used (i.e., 177Lu or 90Y) will provide significantly higher Linear Energy Transfer
(LET) and a shorter path length. Higher LET particles should cause more tumor cell death.
Shorter path length should result in less collateral damage of the normal tissue and
therefore less side effects for subjects receiving the drug.
This dose escalation study will include a maximum of 50 subjects with histologically
confirmed NET, a positive somatostatin analogue scan, and no prior history of PRRT therapy.
The study will begin with a single ascending dose (SAD) of AlphaMedix™ administered by IV.
Subsequent cohorts will receive an incremental 30% increase that will continue until tumor
response or DLT. Once tumor response is observed, the study will convert to a Multiple
Ascending Dose (MAD) regimen. The MAD treatment regimen will start with the previous safe
cohort's dose and will consist of 3 IV administrations of AlphaMedix™ at 8-week intervals.
Subsequent cohorts will receive an incremental 30% increase that will continue until tumor
response or DLT.
The primary objective is to assess the safety and dose limiting toxicity (DLT) using
ascending doses of AlphaMedix™. The secondary objectives are to determine the pharmacokinetic
properties and preliminary effectiveness of AlphaMedix™.
Inclusion Criteria:
- ECOG status 0-2.
- Life expectancy of at least 12 weeks.
- Histologically confirmed diagnosis of SSTR (+) NET, unresectable or metastatic.
- Measurable disease per RECIST 1.1 on CT/MRI scans, defined as at least 1 lesion with ≥
1 cm in longest diameter (LD) (lymph nodes along short axis).
- Appropriate diagnostic imaging studies, at the discretion of the PI including but not
limited to CT, MRI, 18F-FDG PET/CT, NAF PET/CT bone scan, ultrasound, etc. of the
tumor region or suspected area within the 4 weeks of dosing day.
- SSTR(+) disease, as evidenced by available FDA approved SSTR imaging (SRI) within 4
weeks prior to the first cycle.
- All FDA-approved therapies for which the subject is eligible have been exhausted.
- Recent blood test results (within 2 weeks pre-dose) as follows: Sufficient bone marrow
capacity as defined by white blood cell (WBC) ≥2,500/µl and WBC ≥2,000/µl for
subsequent cycles; platelets ≥ 100,000/µl for the first treatment and ≥75,000 for the
subsequent therapies, hemoglobin (HgB) ≥8.9 g/dl for the first treatment and 8.0 g/dl
for the subsequent therapies, ANC ≥1,500/µl for the first treatment and ≥1,000/µl; for
the subsequent therapies; ALT, AST values ≤3 times upper limit of normal (ULN);
Bilirubin: ≤3 times ULN; Serum creatinine ≤150 µmol/liter or 1.7 mg/dl; Negative
pregnancy test in women capable of child-bearing within 48 hours of administration;
Serum albumin > 3.0 g/L (<3.0 g/L may be acceptable at the discretion of PI, if PT,
PTT, and INR are within normal range)
Exclusion Criteria:
- Prior whole-body radiotherapy and PRRT using 177Lu/90Y/111In- DOTATATE/DOTATOC or TAT
- Known hypersensitivity to 68Gallium, Octreotate, or any of the excipients of
68Ga-DOTATATE, AA infusion or AlphaMedix™.
- Therapeutic use of any somatostatin analogue, including Sandostatin® LAR (within 28
days) and Sandostatin® (within 1 day) prior to administration of investigational drug.
- Subjects with unusual hematological parameters, including an increased mean
corpuscular volume (MCV) (>100,000), and especially in those who had previous
chemotherapy, the advice of a hematologist should be sought for adequate further
work-up to rule out myelodysplastic syndrome (MDS).
- Any subject who is taking concomitant medications that decrease renal function (such
as aminoglycoside antibiotics).
- Female subjects who are pregnant, lactating or women of childbearing potential not
willing to practice effective contraceptive techniques during the study period and for
8 weeks post-injection or male subjects who have female partners of childbearing
potential not willing to practice abstinence or effective contraception, during the
study period and for 8 weeks post-injection.
- Current somatic or psychiatric disease/condition that may interfere with the
objectives and assessments of the study.
- Indication for surgical lesion removal with curative potential
- Known brain metastases; unless these metastases have been treated and stabilized 6
months prior to enrollment
- Completion of: (1) cytotoxic chemotherapy for less than 6 weeks; (2) a biological
agent for less than 5 half-lives; and (3) radiation therapy for less than 6 weeks
prior to study enrolment,
- Uncontrolled congestive heart failure; subjects suspected of having this condition
need to show ejection fraction of >55% as determined by multigated acquisition (MUGA)
scan.
- Carcinoid heart disease: Prior history of torsade de pointe, or congenital long QT
syndrome; Conditions with screening ECG repolarization difficult to interpret, or
showing significant abnormalities. This includes, but is not limited to: high degree
AV block, pacemaker, atrial fibrillation or flutter; QTcF interval > 480 msec on
screening ECG; Significant hypokalemia at screening (Potassium <3.5 mMol/L);
Significant hypomagnesemia at screening (Mg++ <0.7 mMol/L)
- GFR < 35 mL/min
