Metastatic Castration Resistant Prostate Cancer
Conditions
Keywords
prostate cancer, PSMA, mCRPC, Phase 1 dose escalation, Phase 1 safety, Phase 2 safety, open-label
Brief summary
This is a phase 1, first-in-human study to evaluate Safety, Tolerability, PK, PD, Immunogenicity, and Antitumor Activity of LAVA-1207 alone or with low dose interleukin-2 or Pembrolizumab, in patients with therapy refractory metastatic castration resistant prostate cancer.
Detailed description
This trial is an open-label Phase 1 dose escalation trial with an expansion cohort to investigate the safety and tolerability of LAVA-1207 alone or with low dose interleukin-2 or Pembrolizumab, in patients with therapy refractory mCRPC. The trial was intended to be a Phase 1/2 trial (but the trial never moved forward to Phase 2).
Interventions
BIOLOGICALLAVA-1207
In part 1 & part 2 • LAVA-1207 will be administered via intravenous infusion.
BIOLOGICALLAVA-1207 plus Pembrolizumab
Pembrolizumab will be administered via intravenous infusion
Sponsors
Merck Sharp & Dohme LLC
Lava Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(for patients receiving LAVA-1207 +/- LDSC IL-2): Patients are eligible to be included in the arm only if all of the following criteria apply: 1. Patient must be 18 years of age inclusive or above, at the time of signing the informed consent. 2. Male patient with mCRPC as defined by PCWG3 criteria (histologically confirmed adenocarcinoma; adenocarcinoma with ≤10% small-cell or neuroendocrine features is allowed). Brain metastases are allowed as long as the patient's symptoms are well controlled. 3. Patient should have failed at least 1 line of taxane-based chemotherapy or is deemed medically unsuitable to be treated with a taxane regimen. 4. Patient should have received a 2nd generation or later androgen receptor targeted therapy/ androgen biosynthesis inhibitor (e.g., abiraterone,enzalutamide, and/or apalutamide). Progression on novel antiandrogen therapy may have occurred in the non-mCRPC setting. 5. Patient is unlikely to tolerate or derive clinically meaningful benefit from other available therapy. 6. Patient for which any drug-related toxicity adverse effects of any prior cancer therapy have resolved to Grade 1 or less according to CTCAE version 5.0 or to baseline severity level (except for alopecia and peripheral neuropathy). 7. Patients with evidence of progressive disease, defined as 1 or more of the following criteria: 1. PSA level ≥1 ng/mL that has increased on at least 2 successive occasions at least 1 week apart. 2. Computed tomography (CT) or magnetic resonance imaging (MRI) scan: nodal or visceral progression as defined by RECIST 1.1. 3. Bone scintigraphy: appearance of 2 or more new metastatic lesions. 8. Patient should have undergone bilateral orchiectomy or should be on continuous androgen-deprivation therapy (ADT) with a gonadotropin-releasing hormone agonist or antagonist (surgical or medical castration). 9. Total serum testosterone ≤ 50 ng/dL or 1.73 nmol/L. 10. Evaluable (measurable or non-measurable) disease for prostate cancer. 11. Predicted life-expectancy of ≥ 6 months. 12. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 13. Adequate renal function (estimated glomerular filtration rate \[eGFR\] per local laboratory \> 40 mL/min/1.73m2), hepatic (bilirubin ≤ 2 times upper limit of normal \[ULN\], aspartate aminotransferase \[AST\] and alanine aminotransferase \[ALT\] ≤3.0 times ULN). In case of liver metastases, AST, and ALT ≤ 5.0 times ULN is allowed. Adequate hematological function (neutrophils \> 1 x 109/L, platelet count \> 75 x 109/L, Hb\>9g/dL) with no prior transfusions within 2 weeks. 14. Males who are: 1. Surgically sterile (bilateral orchiectomy, vasectomy). 2. Compliant with an effective contraceptive regimen (i.e. use of male condom with female partner and assuring use of an additional highly effective contraceptive method with a failure rate of \<1% per year when having sexual intercourse with a woman of childbearing potential who is not currently pregnant) following from signing of the informed consent form \[ICF\] through 90 days after the last IMP administration. Abstinence is not considered an adequate contraceptive regimen. 3. Refraining from donating sperm following the signing of the ICF through 90 days after the last IMP administration. 15. Capable of giving signed and dated informed consent prior to initiation of any trial-related procedures that are not considered Standard of Care which includes compliance with the requirements and restrictions listed in the ICF and in the protocol. INCLUSION CRITERIA (for LAVA-1207 plus pembrolizumab arm): Patients are eligible to be included in the arm only if all of the following criteria apply: 1. Patient must be 18 years of age inclusive or above, at the time of signing the informed consent. 2. Male patient with mCRPC as defined by PCWG3 criteria (histologically confirmed adenocarcinoma; adenocarcinoma with ≤10% small-cell or neuroendocrine features is allowed). Brain metastases are allowed as long as the patient's symptoms are well controlled, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment. 3. Patient should have failed at least 1 line of taxane-based chemotherapy or is deemed medically unsuitable to be treated with a taxane regimen. 4. Patient should have received a 2nd generation or later androgen receptor targeted therapy/androgen biosynthesis inhibitor (e.g., abiraterone, enzalutamide, and/or apalutamide). Progression on novel anti-androgen therapy may have occurred in the non-mCRPC setting. 5. Patient is unlikely to tolerate or derive clinically meaningful benefit from other available therapy. 6. Patient for which any drug related toxicity or adverse effects of any prior cancer therapy should have resolved to Grade 1 or less according to CTCAE version 5.0 or to baseline severity level (except alopecia and peripheral neuropathy). 7. Patient has evidence of progressive disease, defined as 1 or more criteria: 1. PSA level ≥1 ng/mL that has increased on at least 2 successive occasions at least 1 week apart. 2. CT or MRI scan: nodal or visceral progression as defined by RECIST 1.1. 3. Bone scintigraphy: appearance of 2 or more new metastatic lesions. 8. Patient should have undergone bilateral orchiectomy or should be on continuous ADT with a gonadotropin-releasing hormone agonist or antagonist (surgical or medical castration). 9. Total serum testosterone ≤ 50 ng/dL or 1.73 nmol/L. 10. Evaluable (measurable or non-measurable) disease for prostate cancer. 11. Predicted life-expectancy of ≥ 6 months. 12. ECOG performance status of 0 or 1. 13. Adequate renal function (eGFR per local laboratory \> 40 mL/min/1.73m2), hepatic (bilirubin \< 1.5 times ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels \>1.5 × ULN, AST and ALT \<2.5 times ULN). In case of liver metastases, AST, and ALT \< 5.0 times ULN is allowed. Adequate hematological function (neutrophils \> 1.5 x109/L, platelet count \> 100x109/L, Hb\>9g/dL or 5.6 mmol/L, with no prior transfusions within two weeks). 14. Males who are: 1. Surgically sterile (bilateral orchiectomy, vasectomy). 2. Compliant with an effective contraceptive regimen (i.e., use of male condom with female partner and assuring use of an additional highly effective contraceptive method with a failure rate of \<1% per year when having sexual intercourse with a woman of childbearing potential who is not currently pregnant following from signing of the ICF through 90 days after the last IMP administration). Abstinence is not considered an adequate contraceptive regimen. 3. Refraining from donating sperm following the signing of the ICF through 90 days after the last IMP administration. 15. Capable of giving signed and dated informed consent prior to initiation of any trial-related procedures that are not considered Standard of Care which includes compliance with the requirements and restrictions listed in the ICF and in the protocol.
Exclusion criteria
(for patients receiving LAVA-1207 +/- LDSC IL-2): Patients are excluded from the trial if any of the following criteria apply: 1. Other malignancies within the last 2 years except adequately treated carcinoma in situ, basal or squamous cell skin carcinoma. 2. Uncontrolled or severe intercurrent medical condition. 3. Positive serological testing for human immunodeficiency virus (HIV) antibody. 4. Positive serological hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) negative, and hepatitis C virus (HCV) antibody. Patients who are positive for anti-HBc or hepatitis C antibody may be included if they have a negative polymerase chain reaction (PCR) within 6 weeks prior to initial IMP administration. Those who are PCR positive will be excluded. 5. Patient has any active, uncontrolled, or suspected infection. 6. Known clinically relevant immunodeficiency disorders. 7. A significant history of renal, neurologic, psychiatric, pulmonary, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that in the opinion of the investigator would adversely affect participation in this trial. 8. Unstable cardiovascular function defined as: (a) symptomatic ischemia, or (b) uncontrolled clinically significant conduction abnormalities (i.e. ventricular tachycardia on antiarrhythmic agents are excluded; 1st degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block is not excluded), or (c) congestive heart failure New York Heart Association Class ≥ 3, or (d) myocardial infarction within 3 months. 9. Previous treatment with antitumor therapies within 2 weeks prior to initial IMP for radiotherapy and androgen receptor targeted therapy/androgen biosynthesis inhibitor, and within 4 weeks for systemic chemotherapy or targeted immunotherapy. 10. Previous treatment with live or live attenuated vaccines within 2 weeks prior to initial IMP administration. New types of vaccines need to be evaluated as to their mode of action. 11. Treatment with other investigational agents in the 4 weeks prior to initial IMP administration. 12. Major surgery within 4 weeks prior to initial IMP administration. 13. Hypersensitivity to any of the excipients present in LAVA-1207 or IL-2 (if applicable). 14. Previous treatment with any systemic immunosuppressant within 4 weeks prior to initial IMP administration, with the exception of systemic corticosteroid use up to oral dose of 10 mg prednisone daily (or equivalent for other steroids). 15. Previous treatment with an aminobisphosphonate IV (e.g., ibandronate, pamidronate, zoledronate etc.) within 12 months prior to initial IMP. 16. Known ongoing drug and alcohol abuse in the opinion of the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Frequency and type of DLT | First 28 days of treatment | DLT is defined as an adverse event that is unrelated to disease progression, intercurrent illness, or concomitant medications and is occurring during the first 28 days of treatment.illness, or concomitant medications and is occurring during the first 28 days of treatment. |
| Part 1 & Part 2: Frequency and severity of AEs | Approximately 24 months | Frequency and severity of Adverse Events using the Common Terminology Criteria and grading for Adverse Events and grading for CRS |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 & Part 2: Pharmacokinetic of LAVA-1207, area under the concentration versus time curve (AUC) | Approximately 6 months | Area under the plasma concentration versus time curve (AUC) of LAVA-1207 will be assessed in all patients |
| Part 1 & Part 2: Biomarkers, binding of LAVA-1207 to Vγ9Vδ2-T cells | Approximately 24 months | Binding of LAVA-1207 to Vγ9Vδ2-T cells will be measured in whole blood |
| Part 1 & Part 2: Incidence and prevalence of anti-LAVA-1207 antibodies | Approximately 6 months | Development of antibodies (anti-drug antibodies) to LAVA-1207 will be evaluated |
| Part 1 & Part 2: Number of participants with an antitumor response | Approximately 24 months | According to immune Response Evaluation Criteria in Solid Tumors (RECIST and iRECIST) in patients with measurable disease. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory Objective | Approximately 24 months | To evaluate the effect of study treatment on circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) |
Countries
Netherlands, Spain, United States
Outcome results
None listed