Embryonal Carcinoma, Germ Cell Tumors, Nonseminomatous Germ Cell Tumor, Testicular Cancer, Testis Cancer
Conditions
Keywords
Antigens, CD30, Embryonal Germ Cell Tumors
Brief summary
This is a Phase II study to evaluate the activity of brentuximab vedotin in relapsed/refractory non-seminomatous germ cell tumors (NSGCT).
Detailed description
Primary Objective To determine the anti-tumor efficacy of brentuximab vedotin in relapsed/ refractory NSGCT. Secondary Objectives 1. To determine the progression free survival in patients with relapsed/ refractory NSGCT treated with brentuximab vedotin. 2. To determine the overall survival of patients with relapsed/ refractory NSGCT treated with brentuximab vedotin. 3. To determine the safety and tolerability of brentuximab vedotin in this patient population. Eligible patients will be divided into two cohorts, those who are CD30 positive and those who are CD30 negative/unknown. Both groups will be treated similarly and in parallel but analyzed separately. CD30 status may be unknown in the unlikely case of tumor-marker-only relapse or when a fresh tumor biopsy is not feasible, and archival tumor tissue is not obtainable despite efforts to do so. These patients will be included in the CD30 negative cohort for analysis purposes, since statistically NSGCT are more likely to be CD30 negative. The number of such patients with unknown CD30 status should not exceed 5 patients. Eligible patients will be treated with brentuximab vedotin at 1.8 mg/kg IV every 3 weeks (maximum dose of 180 mg) indefinitely until disease progression, unacceptable toxicity, or study closure.Eligible patients with grade 2 peripheral neuropathy at enrollment will be treated with brentuximab vedotin at 1.2 mg/kg IV every 3 weeks (maximum dose of 180 mg) indefinitely until disease progression, unacceptable toxicity, or study closure. Response to treatment will be assessed clinically with history, physical exam and tumor markers measurement (BHCG and AFP) on day 1 of each cycle and with CT scans after cycle 2, 4, and every 4 cycles thereafter while receiving treatment.
Interventions
DRUGBrentuximab Vedotin
Both cohorts will be treated similarly and in parallel but analyzed separately.
Sponsors
Nabil Adra
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subject must meet all of the following applicable inclusion criteria to participate in this study: 1. Age ≥ 18 years at the time of informed consent. 2. Patients with histologically or serologically confirmed relapsed/refractory non-seminoma germ cell tumor, (i.e., embryonal carcinoma, choriocarcinoma, or yolk sac tumors) including female GCT and primary mediastinal NSGCT. 3. Patients must have progressed after prior high dose chemotherapy (HDCT) treatment, been deemed not to be a candidate for high dose chemotherapy or refused high-dose chemotherapy, and be considered incurable by other standard therapies including further chemotherapy or surgery. There is no maximum allowable number of previous therapies. Failure of prior therapy is defined as: 1. A \>25% increase in the products of perpendicular diameters of measurable tumor masses during prior therapy which are not amenable to surgical resection. 2. The presence of new tumors which are not amenable to surgical resection. 3. An increase in AFP or beta-hCG (two separate determinations at least one week apart are required if rising tumor markers are the only evidence of failure). NOTE: Patients with clinically growing teratoma (normal declining tumor markers and radiographic or clinical progression) should be considered for surgery. 4. Patients must have evidence of recurrent or metastatic carcinoma by one or more of the following: i) The appearance of metastatic disease by standard imaging techniques ii) The appearance of rising serum tumor marker, AFP or beta-hCG NOTE: If a rising tumor marker is the only evidence of progressive disease, at least 2 consecutive rising values at least one week apart are needed. Patients with only evidence of disease is rising tumor marker AFP and beta-hCG will be provided alternate causes of increased serum levels of these markers are not present, such as cross reaction with luteinizing Hormone (LH) (that can be tested if needed by testosterone suppression of LH), hepatitis, use of marijuana or second primary tumor, etc. 5. Patients with primary medistinal non seminomatous germ cell tumor are eligible if they have received first line platinum based chemotherapy and their recurrence is not amenable to surgical resection based on the treating physician expert opinion. 6. Patients with late relapse (\>2 years) of non seminomatous germ cell tumors are eligible if they have received first line platinum based chemotherapy and their recurrence is not amenable to surgical resection based on the treating physician expert opinion. 7. Patients with brain metastases are allowed onto the study as long as patients have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomatic. Subjects with neurological symptoms should undergo a head CT scan or brain MRI to exclude brain metastasis, at the discretion of the treating physician. 8. Patients with ECOG performance status of 0-2. 9. Adequate organ and marrow function as defined below: 1. Hemoglobin ≥ 8 g/dL 2. Absolute neutrophil count ≥ 1,000/mm3 3. Platelet count ≥ 75,000/mm3 4. Total bilirubin ≤ 1.5 × ULN except patients with documented Gilbert's syndrome (≤ 3 × ULN) 5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤ 5 × ULN 6. Calculated creatinine clearance ≥ 30 mL/min as determined by the Cockcroft-Gault equation. 10. Patients who are willing and able to comply with the protocol and study procedures including willingness to undergo tumor biopsy for tumor cells before therapy to assess for CD30 status (unless archival tumor tissue from orchiectomy or other previous sample is not obtainable despite efforts to do so and a fresh tumor biopsy is not feasible). 11. Females of childbearing potential must not be pregnant or breast-feeding. Male and female patients of reproductive potential must agree to use two forms of highly effective contraception from the screening visit through 28 days after the last dose of study drug. Acceptable forms of effective contraception include: * Oral, injected or implanted hormonal methods of contraception. * Placement of an intrauterine device (IUD) or intrauterine system (IUS). * Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. * Male sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). * True abstinence: When this is in line with the preferred and usual lifestyle of the subject. \[Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.\] Pregnancy tests for females of childbearing potential are required; must be serum at screening and the post treatment safety assessment visit. A positive urine pregnancy test must be confirmed by a serum pregnancy test and a pelvic US since some NSGCT may secrete beta-hCG and cause a false positive pregnancy. A pelvic US does not need to be repeated with each cycle unless the treating physician thinks it is necessary to do so. 12. Potential subject must have the ability to understand (as judged by the treating physician) and willingness to provide written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Written informed consent must be obtained from a potential subject prior to the conduct of any study-specific procedures.
Exclusion criteria
Subjects meeting any of the criteria below may not participate in the study: 1. Patients with pure seminoma. 2. Patients with pure teratoma. 3. Chemotherapy within 2 weeks of initiating study treatment. There is no maximum allowable number of previous therapies. 4. Major surgery within 3 weeks of starting study treatment. There is no minimum time requirement for minor procedures such as biopsy or vascular access placement. 5. Radiation within 2 weeks of starting study treatment. 6. ≥ Grade 3 neuropathy at the time of enrollment. 7. Pregnancy or breast-feeding. 8. Previous treatment with any anti-CD30 directed therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response (Percent of Patients With Complete Response or Partial Response) | Up to 1 year | Measured by RECIST v1.1 and tumor markers (AFP and BhCG). CR - disappearance of all target lesions and normalization of serum tumor markers for at least 4 weeks. When only evidence of disease is elevated serum tumor markers, then values must fall below the upper limit of normal for the assay and remain at that level for at least 4 weeks. PR - at least a 30% decrease in the sum of the diameters of target lesions compared to the baseline sum diameters for at least 2 measurements 1 month apart with the serum markers as stable/decreasing. When only evidence of disease is elevated serum tumor markers, then values must fall \>=90% below baseline pretreatment levels for BhCG or 50% decrease below baseline pretreatment levels for AFP and persist for 6 weeks. If both tumor markers are elevated and one falls below 90% the other should fall at least below 50% of baseline pretreatment levels.The percent of patients with objective response and its 95% exact confidence interval will be provided. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Up to 2 years | Duration of time from the start of treatment to time of documented progression or death. Patients who did not progress or die were censored on their last evaluation date. Kaplan-Meier methods will be used and the median and 95% confidence intervals will be calculated. |
| Overall Survival | Up to 2 years | Duration of time from the start of treatment to time of death due to any causes. Patients who did not die were censored on their last known alive date. Kaplan-Meier methods will be used and the median and 95% confidence intervals will be calculated. |
| Number of Patients With Treatment Related Adverse Events Grade 3 or Above | Up to 2 years | Number of unique patients who had a treatment related (possible, probable or definite) adverse event with grade \>= 3 using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. |
Countries
United States
Participant flow
Recruitment details
This protocol was a two cohort Phase II study. A Simon two-stage design was used. One cohort (CD30 negative/unknown) met the stopping rule for lack of efficacy at the first stage interim analysis. The first stage of the second cohort (CD30 positive) was not completed because the study was stopped early due to lack of funding.
Participants by arm
| Arm | Count |
|---|---|
| CD30 Negative/Unknown Brentuximab Vedotin 1.8 mg/kg (1.2 mg/kg in patients with grade 2 peripheral neuropathy at enrollment) administered by IV infusion given over approximately 30 minutes on Day 1 of each 21-day cycle for CD30 Negative/Unknown cohort. | 11 |
| CD30 Positive Brentuximab Vedotin 1.8 mg/ kg (1.2 mg/kg in patients with grade 2 peripheral neuropathy at enrollment) administered by IV infusion given over approximately 30 minutes on Day 1 of each 21-day cycle for CD30 Positive cohort. | 7 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 1 |
| Overall Study | Disease Progression | 10 | 6 |
Baseline characteristics
| Characteristic | CD30 Positive | Total | CD30 Negative/Unknown |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 18 Participants | 11 Participants |
| Age, Continuous | 32.2 years STANDARD_DEVIATION 9.18 | 35.9 years STANDARD_DEVIATION 9.35 | 38.2 years STANDARD_DEVIATION 9.09 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 16 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 6 Participants | 13 Participants | 7 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 7 Participants | 17 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 11 | 6 / 7 |
| other Total, other adverse events | 11 / 11 | 7 / 7 |
| serious Total, serious adverse events | 2 / 11 | 3 / 7 |
Outcome results
Primary
Objective Response (Percent of Patients With Complete Response or Partial Response)
Measured by RECIST v1.1 and tumor markers (AFP and BhCG). CR - disappearance of all target lesions and normalization of serum tumor markers for at least 4 weeks. When only evidence of disease is elevated serum tumor markers, then values must fall below the upper limit of normal for the assay and remain at that level for at least 4 weeks. PR - at least a 30% decrease in the sum of the diameters of target lesions compared to the baseline sum diameters for at least 2 measurements 1 month apart with the serum markers as stable/decreasing. When only evidence of disease is elevated serum tumor markers, then values must fall \>=90% below baseline pretreatment levels for BhCG or 50% decrease below baseline pretreatment levels for AFP and persist for 6 weeks. If both tumor markers are elevated and one falls below 90% the other should fall at least below 50% of baseline pretreatment levels.The percent of patients with objective response and its 95% exact confidence interval will be provided.
Time frame: Up to 1 year
Population: All patients who received at least one dose of study medication and at least one evaluable assessment after treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CD30 Negative/Unknown | Objective Response (Percent of Patients With Complete Response or Partial Response) | 0 percentage of patients |
| CD30 Positive | Objective Response (Percent of Patients With Complete Response or Partial Response) | 0 percentage of patients |
Secondary
Number of Patients With Treatment Related Adverse Events Grade 3 or Above
Number of unique patients who had a treatment related (possible, probable or definite) adverse event with grade \>= 3 using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Time frame: Up to 2 years
Population: All patients who received at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CD30 Negative/Unknown | Number of Patients With Treatment Related Adverse Events Grade 3 or Above | 0 Participants |
| CD30 Positive | Number of Patients With Treatment Related Adverse Events Grade 3 or Above | 2 Participants |
Secondary
Overall Survival
Duration of time from the start of treatment to time of death due to any causes. Patients who did not die were censored on their last known alive date. Kaplan-Meier methods will be used and the median and 95% confidence intervals will be calculated.
Time frame: Up to 2 years
Population: All patients who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CD30 Negative/Unknown | Overall Survival | 5.89 months |
| CD30 Positive | Overall Survival | 2.53 months |
Secondary
Progression Free Survival
Duration of time from the start of treatment to time of documented progression or death. Patients who did not progress or die were censored on their last evaluation date. Kaplan-Meier methods will be used and the median and 95% confidence intervals will be calculated.
Time frame: Up to 2 years
Population: All patients who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CD30 Negative/Unknown | Progression Free Survival | 1.38 months |
| CD30 Positive | Progression Free Survival | 1.15 months |