Metastatic Cancer
Conditions
Brief summary
Participants with metastatic cancer who are taking anti-PD-1 or anti-PD-L1 therapy will be enrolled to assess the safety of and find the optimal dose for radioactive imaging agents and to explore whether these agents will make current drug therapies work better. Up to 60 participants will be enrolled and can expect to be on study for up to 9 months.
Detailed description
This is a safety study of 86Y-NM600 and 90Y-NM600 and a dose finding study for 90Y-NM600 in patients with metastatic cancers who are receiving an anti-PD-1 or anti-PD-L1 therapy, have persistent disease that is stable or potentially progressive, and will be continuing anti-PD-1 or anti-PD-L1 therapy for another imaging interval per the treating physician. The imaging agent 86Y-NM600 will be injected, and serial positron-emission tomography (PET)/computed tomography (CT) imaging will be performed to enable dosimetry calculations that will be used to determine eligibility for 90Y-NM600. Phase 1a of the study (dose finding) will enroll 6-24 participants into a 3x3 dose finding plan where 3 participants start at Level 1 (below) and the number of participants with dose limiting toxicities (DLTs) will inform the next 3 participants: * 0/3 Escalate to next higher dose level\* * 1/3 Accrue additional 3 patients at current dose level * 1/3 + 0/3 Escalate to next higher dose level\* * 1/3 + ≥ 1/3 End phase 1a or de-escalate to dose level -1 if at dose level 1 * ≥ 2/3 End phase 1a or de-escalate to dose level -1 if at dose level 1 Dosing Plan: * Level -1: 20 millicurie (mCi) x 1 * Level 1: 35 mCi x1 * Level 2: 70 mCi x1 * Level 3: 105 mCi x1 * Level 4: 140 mCi x1 Phase 1b (expansion cohort) may enroll up to an additional 36 participants (18 into a single dose cohort, 18 into a multi-dose cohort) with metastatic cancer. The primary endpoints are to determine the safety of administering 86Y-NM600 for imaging and 90Y-NM600 for delivering radiation in patients with metastatic cancer who are receiving standard-of-care anti-PD-1 or anti-PD-L1 therapy.
Interventions
DRUG90Y-NM600
NM600 is a tumor-selective, pan-cancer, targeted radionuclide therapy (TRT) with theranostic capacity
Sponsors
University of Wisconsin, Madison
Archeus Technologies, Inc.
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
3x3 dose escalation
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participant must be informed of the investigational nature of the study and must be able to sign a written informed consent. 2. Participants with histologically or cytologically confirmed squamous cell carcinoma thought to originate from the head and neck region (HNC). 3. Participants must have metastatic solid malignancy, non-hematological. 4. Participants must be under treatment with one of the following FDA-approved standard-of-care anti-PD-1 or anti-PD-L1 therapies: Pembrolizumab (Keytruda; anti-PD-1 antibody), Nivolumab (Opdivo; anti-PD-1 antibody), Atezolizumab (Tecentriq, anti-PD-L1 antibody), Avelumab (Bavencio; anti-PD-L1 antibody), Durvalumab (Imfinzi; anti-PD-L1 antibody), Cemiplimab (Libtayo; anti-PD-1 antibody), Dostarlimab (Jemperli; anti-PD-1 antibody). Participants may be on additional FDA-approved immunotherapy treatments including anti-CTLA4 therapies or anti-LAG-3 therapies in addition to the anti-PD-1 or anti-PD-L1 backbone therapy. The specific additional therapies allowed are: Ipilimumab (Yervoy; anti-CTLA4 antibody), Tremelimumab (Imjudo; anti-CTLA4 antibody), or Relatlimab (Opdualag; anti-LAG-3). 5. Participants must have stable disease or concern for progression of their disease on most recent imaging scans yet be continuing on anti-PD1 or anti-PD-L1 therapy, per the treating physician. Participants may continue on anti-CTLA-4 or anti-LAG-3 ICIs if they have already been taking these when assessed to have stable or potentially progressive disease on most recent imaging. Subjects may also discontinue anti-CTLA-4 or anti-LAG-3 ICIs and remain eligible as long as they meet above criteria and continue the anti-PD-1 or anti-PD-L1 component of therapy that they have already been taking. 6. Participants must have at least one evaluable (measurable) tumor that is radiographically detectable. 7. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2. 8. Participants must have a life expectancy of at least 6 months. 9. People who could become pregnant have a confirmed negative urine pregnancy test within 7 days prior to receiving Y-NM600. 10. Participants who are not surgically or medically sterile must agree to use an acceptable method of contraception, such as an oral, implantable, injectable, or transdermal hormonal contraceptive, an intrauterine device (IUD), a double barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), or total abstinence during the study participation and for 6 months after last dose of study drug. Participants who could impregnate their sexual partners must also abstain from intercourse for three weeks after Y-NM600 treatment and agree to use condoms at least 2 months after the last dose of this drug. Participants who are postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) are not considered to be people who could become pregnant. 11. The participant has adequate renal function as defined by Cockcroft-Gault calculated creatinine clearance \>40 ml/min 12. The subject has adequate hepatic function as defined by: 1. total bilirubin ≤ 1.5 times the upper limit of normal (ULN) 2. aspartate transaminase (AST) and alanine transaminase (ALT) less than or equal to 3.0 times the ULN 13. The participant has adequate hematologic function without Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) injection or transfusion in the prior 7 days, as evidenced by: 1. an absolute neutrophil count (ANC) greater than or equal to 2000 / μL 2. hemoglobin greater than or equal to 8 g/dL 3. platelets greater than or equal to 100,000 / μL 14. For phase 1a, participant must be willing to undergo 2 core needle biopsies that are accessible via ultrasound and/or clinical biopsy. 15. Adequate uptake of 86Y-NM600 (2x red bone marrow) on PET CT imaging. 16. No grade 2 toxicities that are new compared to baseline and lack a possible alternative explanation (e.g., underlying disease or another known cause) were noted by Day 7 after the 86Y-NM600 infusion. Toxicities with at least a possibly related attribution to disease and/or another cause-even if also considered at least possibly related to 86Y-NM600-are permitted. 17. No Grade ≥ 3 toxicities that are new compared to baseline were noted by day 7 after 86Y-NM600 infusion.
Exclusion criteria
1. Other concurrent severe and/or uncontrolled concomitant medical or psychiatric conditions (e.g., active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol, per investigator discretion. 2. The participant is taking strong inducers or inhibitors of CYP450 enzymes or drug transporters that cannot be held from at least 30 days prior to administration of 86Y-NM600 through the final 90Y-NM600 infusion without any expected adverse events. Examples include: clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, phenobarbital, phenytoin, rifampicin, and glucocorticoids. 3. Chemotherapy, radiotherapy, or major surgery within 3 weeks prior to study enrollment (this will be greater than 5 weeks prior to 90Y-NM600 therapy). a. For patients receiving prior radiation therapy, the dose to tumor, kidneys, liver, and bone marrow must be recorded, if available. 4. The participant is pregnant, breastfeeding, or expecting to conceive or could impregnate someone within the projected duration of the trial, starting with the screening visit through 6 months after the last dose of trial treatment. 5. Any ongoing or active infection, including active tuberculosis, hepatitis B or C, or known infection with the human immunodeficiency virus (HIV) that is not well controlled (undetectable viral load by PCR) by anti-retroviral therapy. 6. Concurrent treatment with any other systemic anti-cancer or investigational agents other than an anti-PD-1, anti-PD-L1, anti-CTLA-4, or anti-LAG-3 antibody. Subjects cannot be receiving concomitant chemotherapy, experimental therapy or any other therapy not otherwise outlined by the trial for the purposes of anti-cancer treatment. b. Palliative external beam radiation therapy may be delivered to patients during this study if deemed necessary and safe by the treating physician. c. Participants can be receiving dual immune checkpoint inhibition with an anti-CTLA-4 antibody or an anti-LAG-3 antibody in addition to an anti-PD-1 or anti-PD-L1 therapy. 7. Patients with a history of or concurrent second primary malignancy within 2 years to study enrollment are excluded, with the exception of patients who have had definitive treatment of a primary skin basal cell, skin squamous cell carcinomas, or localized low or intermediate risk prostate cancer - these subjects are eligible 3 months after completion of definitive treatment for that prior cancer. 8. Participants that have had total body or hemibody irradiation, or have had prior systemic radioisotope therapy (except for benign thyroid disease) 9. Any condition requiring the use of immunosuppression, excluding rheumatologic conditions or endocrine conditions treated with stable doses of corticosteroids (equivalent to prednisone 10 mg daily) 10. Ongoing hemodialysis or peritoneal dialysis 11. Any known medical condition that predisposes the subject to uncontrolled bleeding such as hemophilia or clotting factor deficiencies 12. Participants with known genetic conditions causing pre-disposition to RT toxicity (i.e.: Li-Fraumeni, ataxia telangiectasia mutated (ATM) deficiency, active scleroderma, active inflammatory bowel disease, active systemic lupus) 13. Patients with an implanted defibrillator or with an implanted pacemaker and pacemaker dependency for rate or rhythm control 14. Patients with repeated demonstration on two EKGs of a QTcF interval greater than 470 milliseconds or use of medications known to prolong the QT/QTc interval 15. Participants who cannot provide independent, legal, informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Toxicities greater than or equal to Grade 3 at least possibly related to 86Y-NM600 | baseline screening, Day 7 after 86Y-NM600 injection | Toxicities greater than or equal to Grade 3 at least possibly related to 86Y-NM600 by day 7 (greater than 10 half-lives of 86Y) after 86Y-NM600 injection, as defined by the NCI CTCAE version 5.0. |
| Toxicities greater than or equal to Grade 3 at least possibly related to 90Y-NM600 | up to 9 months on study | Toxicities greater than or equal to Grade 3 at least possibly related to 90Y-NM600 by day 42 after final 90Y-NM600 injection, as defined by the NCI CTCAE version 5.0. Time points of investigation include: * baseline screening * Phase 1A: post injection week 1, week 2, week 3, week 4 * Phase 1B: 7 days after each injection, 30 days and 42 days after final injection |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of Y-NM600: Blood concentration verse time curve | 3-5 min after end of infusion, 0.5 hours, *2.0 hours, 4.0 hours, 24 hour, and *48 hours after infusion (*Phase 1A only) | Blood concentration verse time curve, blood draws at estimated Cmax 3-5 min after end of infusion, 0.5 hours, \*2.0 hours, 4.0 hours, 24 hour, and \*48 hours after infusion (\*Phase 1A only) |
| Pharmacokinetics of Y-NM600: Time to reach maximum concentration of Y-NM600 in Blood | Blood draws at estimated Cmax 3-5 min after end of infusion, 0.5 hours, *2.0 hours, 4.0 hours, 24 hour, and *48 hours after infusion (*Phase 1A only) | Blood draws at estimated Cmax 3-5 min after end of infusion, 0.5 hours, \*2.0 hours, 4.0 hours, 24 hour, and \*48 hours after infusion (\*Phase 1A only) |
| Pharmacokinetics of Y-NM600: Blood Radioactivity from Y-NM600 | Blood draws at estimated Cmax 3-5 min after end of infusion, 0.5 hours, *2.0 hours, 4.0 hours, 24 hours, and *48 hours after infusion (*Phase 1A only) | Blood draws at estimated Cmax 3-5 min after end of infusion, 0.5 hours, \*2.0 hours, 4.0 hours, 24 hour, and \*48 hours after infusion (\*Phase 1A only) |
| Pharmacokinetics of Y-NM600: Physiological Half-life of Y-NM600 | Blood draws at estimated Cmax 3-5 min after end of infusion, 0.5 hours, *2.0 hours, 4.0 hours, 24 hours, and *48 hours after infusion (*Phase 1A only) | Phase 1a: Blood draws at estimated Cmax 3-5 min after end of infusion (+/- 5 min), 0.5 hours (+/- 15 min), 2.0 hours (+/- 30 min), 4.0 hours (+/- 30 min), 24 hours (+/- 120 min), and 48 hours (+/- 120 min) after infusion. Phase 1b: Blood draws at estimated Cmax 3-5 min after end of infusion (+/- 5 min), 0.5 hours (+/- 15 min), 4.0 hours (+/- 30 min), and 24 hours (+/- 120 min) after infusion. Cumulative urine collection will be done for 6 hours with specific samples collected and pooled at 0.5 hours (+/- 15 min), 3 hours (+/- 30 min), and at 5 hours (+/- 30 min) after infusion. |
| Proportion of Participants with 2-fold or greater uptake of 86Y-NM600 in tumor site compared to red bone marrow | 48-72 hours after 86Y-NM600 infusion | Assessed via PET/CT 48-72 hours after 86Y-NM600 infusion as Maximum Standardized Uptake Value (SUVmax) at tumor sites previously identified by standard of care imaging and at a site of red bone marrow. |
| Overall Response Rate (ORR) by iRECIST at 12 weeks after final 90Y-NM600 injection (D1) | baseline, standard-of-care imaging 12 weeks after D1 | ORR will include iCR and iPR and will be determined as per iRECIST, by investigator assessment. |
| Safe and Effective Dose Level for Phase 1B | Phase 1A: baseline, Once per week for four weeks after 90Y-NM600 injection and at day 42 after 90Y-NM600 injection, Standard-of-care imaging 8 weeks after D1 of 90Y-NM600 | A recommended phase 1b single treatment dose level is based on the following criteria: 1) a dose level resulting in less than 33 percent of participants with Dose Limiting Toxicities by 42 days after final 90Y-NM600 injection, 2) the dose level with the greatest ORR among dose levels that meet criteria 1 and the lower dose level if ORR is equal at two dose levels, and 3) the highest dose level that meets criteria 1 if no participants exhibit ORR in any regimen that meets criterion 1. For the multi-dose expansion cohort, the recommended dose will be the single treatment expansion dose level or the next highest dose level for which OLINDA calculations from PET/CT imaging at 48-72 hours after 86Y-NM600 for all enrolled patients predict cumulative mean doses of less than 23 Gy to the kidney, less than 2 Gy to the red bone marrow, and less than 30 Gy to liver in greater 66 percent of participants following three cycles of 90Y-NM600 at the multi-dose expansion cohort dose level. |
Countries
United States
Contacts
CONTACTCancer Connect
PRINCIPAL_INVESTIGATORGrace Blitzer, MD
UW Carbone Cancer Center
PRINCIPAL_INVESTIGATORJustine Bruce, MD
UW Carbone Cancer Center
STUDY_CHAIRZachary Morris, PhD
UW Carbone Cancer Center
STUDY_CHAIRPaul Harari, MD
UW Carbone Cancer Center
Outcome results
None listed