Past Clinical Trials

BRIEF SUMMARY

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.

Primary Outcome Measures :

1. To determine dose-limiting toxicity (DLT) [ Time Frame: 8 weeks ] DLT is defined as non-hematological toxicity - all Grade 4 and Grade 3 (except alk. phos.) that is not responsive to NMT 72 hours of supportive care - and all hematological toxicity that does not recover to NMT than Grade 2 within 8 wks of dose administration.

2. To determine the maximum tolerated dose (MTD) [ Time Frame: 8 weeks ] The MTD is the dose level below that which 2 out of 6 subjects in a cohort have DLT.

Eligibility Criteria

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 (

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 • GFR < 35 mL/min

Study Evaluating metastatic Castration Resistant Prostate Cancer (mCRPC) Treatment Using PSMA [Lu-177]-PNT2002
Therapy After Second-line Hormonal Treatment (SPLASH)

DETAILED DESCRIPTION

The primary objective of the study is to determine the efficacy of [Lu-177]-PNT2002 ([Lu-177]-PSMA-I&T) versus abiraterone or enzalutamide in delaying radiographic progression in patients with mCRPC. The study consists of 3 phases: Dosimetry, Randomized Treatment, and Long term Follow up. The study will commence with a 25-patient safety and dosimetry lead-in (Part 1) and proceed to a randomization treatment phase in approximately 390 patients (Part 2). Patients in Part 2 will be randomized in a 2:1 ratio to receive either [Lu-177]-PNT2002 (Arm A), or enzalutamide or abiraterone (Arm B). Patients in Arm B who experience radiographic progression per central review and meet protocol defined eligibility, may crossover to receive [Lu-177]-PNT2002. All patients will be followed in long-term follow-up for at least 5 years from the first therapeutic dose, death, or loss to follow up (Part 3). Only patients that meet PSMA PET avidity criteria per central review will be eligible for this study.

Primary Outcome Measures :

1. Radiographic Progression Free Survival (rPFS) [ Time Frame: 32 weeks ] Time in months from the date of randomization to radiological progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (soft tissue) or confirmed progression on bone scan assessed by Prostate Cancer Working Group 3 (PCWG3) (bone), or death from any cause, as assessed by blinded independent central review (BICR).

Eligibility Criteria

Inclusion Criteria:

1. Male aged 18 years or older.
2. Histological, pathological, and/or cytological confirmation of adenocarcinoma of the prostate.
3. Ineligible or averse to chemotherapeutic treatment options.
4. Patients must have progressive mCRPC at the time of consent based on at least 1 of the following criteria:
a. Serum/plasma PSA progression defined as increase in PSA greater than 25% and >2 ng/mL above nadir, confirmed by progression at 2 time points at least 3 weeks apart.
b. Soft-tissue progression defined as an increase ≥20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or a new lesion.
c. Progression of bone disease: evaluable disease or one new bone lesion by bone scan

5. Previous treatment with one ARAT (abiraterone or enzalutamide or darolutamide or apalutamide) in either the CSPC or CRPC setting.
6. PSMA-PET scan (i.e., 68Ga-PSMA-11 or 18F-DCFPyL) positive as determined by the sponsor's central reader.
7. Castrate circulating testosterone levels ( 8. Adequate organ function, independent of transfusion:

a. Bone marrow reserve: i. White blood cell (WBC) count ≥2.5 × 109/L OR absolute neutrophil count (ANC) ≥1.5 × 109/L.
ii. Platelets ≥100 × 109/L. iii. Hemoglobin ≥8 mmol/L. b. Liver function: i. Total bilirubin ≤1.5 × institutional upper limit of normal (ULN). For patients with known Gilbert's syndrome, ≤3 × ULN is permitted.
ii. ALT or AST ≤3.0× ULN. c. Renal function: i. Serum/plasma creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min based on Cockcroft-Gault formula.
d. Albumin ≥30 g/L.

9. Human immunodeficiency virus-infected patients who are healthy and have a low risk of acquired immunodeficiency syndrome-related outcomes are included in this trial.
10. For patients who have partners of childbearing potential: Partner and/or patient must use a method of birth control with adequate barrier protection, deemed acceptable by the principal investigator during the study and for 6 months after last study drug administration.
11. Willing to initiate ARAT therapy (either enzalutamide or abiraterone), pre-specified by investigator, if randomized to Treatment Arm B.
12. ECOG performance status 0 to 1.
13. Willing and able to comply with all study requirements and treatments (including 177Lu PNT2002) as well as the timing and nature of required assessments.
14. Signed informed consent.

Exclusion Criteria:

Patients are excluded from the study if any of the following criteria apply: 1. Prostate cancer with known significant (>10%) sarcomatoid or spindle cell or neuroendocrine components. Any small cell component in the cancer should result in exclusion.
2. Prior treatment for prostate cancer ≤28 days prior to randomization, with the exclusion of first-line local external beam, ARAT, luteinizing hormone-releasing hormone (LHRH) therapy, or non-radioactive bone-targeted agents.
3. Any prior cytotoxic chemotherapy for CRPC (e.g., cabazitaxel or docetaxel); chemotherapy for hormone-sensitive prostate cancer (HSPC) is allowed if the last dose was administered >1 year prior to consent.
4. Prior treatment with systemic radionuclides (e.g. radium-223, rhenium-186, strontium 89).
5. Prior immuno-therapy, except for sipuleucel-T.
6. Prior PSMA-targeted radioligand therapy, e.g., Lu-177-PSMA-617, I 131-1095.
7. Prior poly ADP ribose polymerase (PARP) inhibitor for prostate cancer.
8. Patients who have had 2 or more lines of ARATs.
9. Patients receiving bone-targeted therapy (e.g. denosumab, zoledronic acid) must be on stable doses for at least 4 weeks prior to randomization.
10. Administration of an investigational agent ≤60 days or 5 half-lives, whichever is shorter, prior to randomization.
11. Major surgery ≤30 days prior to randomization.
12. Estimated life expectancy 13. Presence of liver metastases >1 cm on abdominal imaging.
14. A superscan on bone scan defined as a bone scan that demonstrates markedly increased skeletal radioisotope uptake relative to soft tissues in association with absent or faint genitourinary tract activity71.
15. Use of opioids for cancer-related pain ≤30 days prior to consent.
16. Known presence of central nervous system metastases.
17. Contraindications to the use of planned ARAT therapy.
18. Active malignancy other than low-grade non-muscle-invasive bladder cancer and non melanoma skin cancer.
19. Concurrent illness that may jeopardize the patient's ability to undergo study procedures.
20. Serious psychological, familial, sociological, or geographical condition that might hamper compliance with the study protocol and follow-up schedule. Patients that travel need to be capable of repeated visits even if they are on the control arm.
21. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.
22. Concurrent serious (as determined by the investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure (see 12.1 Appendix 1), unstable ischemia, uncontrolled symptomatic arrhythmia, history of congenital prolonged QT syndrome, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation.

BRIEF SUMMARY

Determine the safety and effectiveness of Lu-177 DOTATOC in adult subjects with somatostatin receptor-expressing Pulmonary, Pheochromocytoma, Paraganglioma, Unknown primary, and Thymus neuroendocrine tumors or any other non-.GEP-NET. The treatment regimen will consist of 4 doses of 200 (±10%) mCi 177Lu-DOTATOC administered at 8+/- 1-week intervals

Eligibility Criteria

Inclusion Criteria:

• Signed informed consent.
• Subjects of either sex, aged ≥18 years.
• ECOG status 0-2.
• Life-expectancy of at least 12 weeks.
• Histologically/cytologically confirmed diagnosis of SSTR (+) neuroendocrine tumors of the lung, Pheochromocytoma, Paraganglioma, thymus, and unknown primary, 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 (lymph nodes along short axis >15 mm).
• Appropriate diagnostic imaging studies, at the discretion of the P.I. 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.
• Somatostatin receptor positive (SSTR+) disease, as evidenced by available FDA, commercially of IND approved SSTR imaging (SRI), within 4 weeks prior to the first cycle
• Recent blood test results (within 2weeks pre-dose) as follows:
• Sufficient bone marrow capacity as defined by WBC ≥2,500/µl and WBC≥2,000/mm3 for subsequent cycles; platelets ≥ 100,000 (100 * 103/mm3) for the first treatment and ≥75,000 for the subsequent therapies, Hgb ≥8.9 g/dl for the first treatment and 8.0 g/dl for the subsequent therapies, ANC ≥1500/mm3 for the first treatment and ≥1000/ mm3; for the subsequent therapies.
• ALT, AST values ≤3 times 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 IMP administration.
• Serum albumin > 3.0g/L ( • All available FDA-approved therapies for which the subject is eligible have been exhausted (with the exception of PRRT), unless available therapies are refused by the subject (with the exception of somatostatin analogue, octreotide, and somatuline).

Exclusion Criteria:

• Known hypersensitivity to any of the excipients of Lu-177 DOTATOC.
• Therapeutic use of any somatostatin analogue, including Sandostatin® LAR (within 28 days) and Sandostatin® (within 1 day) prior to treatment.
• Subjects with unusual hematological parameters, including an increased MCV (>105fL), and especially in those who had previous chemotherapy, the advice of a hematologist should be sought for adequate further work-up
• 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 67 days (more than 10 half-lives of 177Lu after the last treatment, or male subjects who have female partners of childbearing potential not willing to practice abstinence or effective contraception, during the study period and for 67 days after the last treatment.
• 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
• Planned (for the period of study participation): chemotherapy, immunotherapy, radiation therapy (unless regional for pain relief) chemo-embolization, bland embolization, radio-embolization, treatment with cyclosporine-A.
• Known brain metastases; unless these metastases have been treated and stabilized 6 months prior to enrolment
• Completion of: (1) cytotoxic chemotherapy for less than 6 weeks; (2) a biological agent for less than 5 half-lives; and (3) radiation therapy (except regional for pain relief) 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 > 35% as determined by MUGA scan.
• Glomerular Filtration Rate (GFR) < 35 mL/min

INDICATION

Patients with suspected prostate cancer recurrence and non-informative bone scintigraphy, computerized tomography (CT) or magnetic resonance imaging (MRI). Suspected prostate recurrence is based upon elevated blood prostate specific antigen (PSA) levels following initial therapy.

Endpoints or Outcome measures:

Primary Outcome measures:

A. The sensitivity of 68Ga-PSMA-11 PET for detection of tumor location. [ Time Frame: 12 months ]

B. The sensitivity of 68Ga-PSMA-11 PET to detect tumor location and metastases in patients with biopsy confirmed diagnosis. Tumor location confirmed by histopathology/biopsy and conventional imaging follow-up.

Secondary Outcome measures:

Detection rates of 68Ga-PSMA-11 PET in patients with different PSA value [ Time Frame: 12 months ]

Detection rates of 68Ga-PSMA-11 PET in patients with different PSA value (0.2 - <0.5, 0.5 - <1.0, 1.0 - <2.0, 2.0 - <5.0, 5.0).

Inclusion Criteria:

General requirements:

1. Karnofsky performance status of ≥50 (or ECOG/WHO equivalent).
2. Age > 18 years .
3. Ability to understand a written informed consent document, and the willingness to sign it.
4. i. inclusion criteria specific for the pre-prostatectomy group: Biopsy proven prostate adenocarcinoma. Planned prostatectomy with lymph node dissection. Intermediate to high-risk disease (as determined by elevated PSA [PSA>10], T-stage [T2b or greater], Gleason score [Gleason score > 6] or other risk factors).
• Histopathological proven prostate adenocarcinoma.
• Rising PSA after definitive therapy with prostatectomy or radiation therapy (external beam or brachytherapy).

1. Post radical prostatectomy (RP) - AUA recommendation, PSA greater than or equal to 0.2 ng/mL measured more than 6 weeks after RP.
2. Post-radiation therapy -ASTRO-Phoenix consensus definition, Nadir + greater than or equal to 2 ng/mL rise in PSA 5. Diagnostic CT or MRI as part of the PET study or performed within one month of PSMA PET .

Exclusion Criteria:

General requirements:

1. Patients not capable of getting PET study due to weight, claustrophobia, or inability to lay still for the duration of the exam.
2. Contraindication to furosemide administration including prior allergy or adverse reaction to furosemide or sulfa drugs. (Note: This exclusion criterion can be removed if Furosemide is omitted as part of the PET imaging protocol if a second-generation scatter correction is available for the used PET device).
3. i. Exclusion criteria specific for the pre-prostatectomy group: Neoadjuvant chemotherapy or radiation therapy prior to prostatectomy, including focal ablation techniques (HiFu) within the last 2 months.
3. ii. Exclusion criteria specific for biochemical recurrence group:
• Investigational therapy for prostate cancer for less than 2 months.
• Prior history of any other malignancy within the last 2 years, other than skin basal cell or cutaneous superficial squamous cell carcinoma that has not metastasized and superficial bladder cancer.

BRIEF SUMMARY

The purpose of the study is to evaluate efficacy and safety of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-Edotreotide compared to targeted molecular therapy with Everolimus in patients with inoperable, progressive, somatostatin receptor-positive (SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin (GEP-NET).

Outcome Measures :

Primary Outcome Measures :

1. progression-free survival (PFS) [ Time Frame: 12 weeks +/- 14 days, up to 24 months ]

PFS will be assessed individually per patient from date of randomization until the date of first documented progression, assessed up to 24 months, primary outcome will be measured by CT/MRI every 12 weeks +/- 14 days.

Secondary Outcome Measures :

1. overall survival (OS) [ Time Frame: every 3 months for a period of at least 24 months ]

OS as secondary outcome measure will be assessed per patient from date of randomization until the date of death, whichever came first

Inclusion Criteria

• Histologically and clinically confirmed diagnosis of well-differentiated neuro-endocrine tumour of non-functional gastroenteric origin (GE-NET) or both functional or non-functional pancreatic origin (P-NET)
• Measurable disease per RECIST 1.1
• Somatostatin receptor positive (SSTR+) disease
• Radiological disease progression, defined as progressive disease per RECIST 1.1. criteria

Exclusion Criteria:

• Known hypersensitivity to edotreotide or everolimus
• Known hypersensitivity to DOTA, lutetium-177, or any excipient of edotreotide or everolimus or any other Rapamycin derivative
• Prior exposure to any peptide receptor radionuclide therapy (PRRT)
• Prior therapy with mTor inhibitors
• Prior EFR (external field radiation) to GEP-NET lesions or radioembolisation therapy
• Therapy with an investigational compound and/or medical device within 30 days prior to randomisation
• Indication for surgical lesion removal with curative potential
• Planned alternative therapy (for the period of study participation)
• Serious non-malignant disease
• Renal, hepatic, cardiovascular, or haematological organ dysfunction, potentially interfering with the safety of the study treatments
• Pregnant or breast-feeding women
• Subjects not able to declare meaningful informed consent on their own (e.g. with legal guardian for mental disorders) or any other vulnerable population to that sense (e.g. persons institutionalised, incarcerated etc.).