Pembrolizumab in Subjects With Incurable Platinum-Refractory Germ Cell Tumors

• Sponsor: Nasser Hanna, M.D. (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02499952
• Collaborator: Hoosier Cancer Research Network (Other), Merck Sharp & Dohme LLC (Industry)
• Enrollment: 12
• Locations: 2
• Arm: 1
• Actual Duration (Months): 12.4
• Patients Per Site: 6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This is an open label, multi-institutional, single arm phase II trial of pembrolizumab in patients with incurable platinum refractory germ cell tumors. No randomization or blinding is involved.

Condition or Disease	Intervention/Treatment	Phase
Germ Cell Neoplasms; Testicular Neoplasms; Non Seminomatous Germ Cell Tumors; Mediastinal Neoplasms; Genital Neoplasms, Male; Genital Neoplasms, Female; Ovarian Neoplasms	Drug: Pembrolizumab	Phase 2

Detailed Description

OUTLINE: This is a multi-center study.

Eligible subjects must have received initial cisplatin-based combination therapy, such as bleomycin-etoposide-cisplatin (BEP), cisplatin-etoposide (EP), etoposide-ifosfamide-cisplatin (VIP), or similar regimens AND demonstrated progression following the administration of at least one 'salvage' regimen for advanced germ cell neoplasm, such as high dose chemotherapy, paclitaxel-ifosfamide-cisplatin (TIP), or vinblastine-ifosfamide-cisplatin (VeIP).

INVESTIGATIONAL TREATMENT:

Pembrolizumab 200mg IV every 3 weeks until progression or toxicity. Treatment will continue for up to 52 weeks in the absence of prohibitive toxicities or disease progression.

The following screening labs to demonstrate adequate organ function must be performed within 10 days of treatment initiation:

Hematological:

• Absolute neutrophil count (ANC) ≥1,500 /mcL

• Platelets ≥100,000 / mcL

• Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or hematopoietin (EPO) dependency (within 7 days of assessment)

Renal:

• Serum creatinine ≤1.5 X upper limit of normal (ULN) OR

• Measured or calculated creatinine clearance ≥60 mL/min for subject with creatinine levels >1.5 X institutional ULN

• Glomerular filtration rate (GFR) can also be used in place of creatinine or creatinine clearance (CrCl)

Hepatic:

• Serum total bilirubin ≤ 1.5 X ULN OR

• Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN

• AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

• Albumin >2.5 mg/dL

Coagulation:

• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

• Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Single-Arm Multi-Center Trial Evaluating the Efficacy of Pembrolizumab in the Treatment of Subjects With Incurable Platinum-Refractory Germ Cell Tumors: Hoosier Cancer Research Network GU14-206
• Actual Study Start Date: Jan 1, 2016
• Actual Primary Completion Date: Jan 13, 2017
• Actual Study Completion Date: Jan 13, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental Arm Pembrolizumab	Drug: Pembrolizumab; 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or after 52 weeks of therapy.; Other Names: MK-3475

Outcome Measures

Primary Outcome Measures

1. Clinical Benefit Rate (CBR) [up to 18 weeks]

   CBR of single agent pembrolizumab in subjects with refractory germ cell tumors (GCTs), determined by sum of complete responses, partial responses, and stable disease for at least 3 months using Immune Related Response Criteria (irRC). Complete Response(irPR): Disappearance of all lesions in two consecutive observations not less than 4 wk apart. Partial Response (irPR): decrease in tumor burden ≥50 %relative to baseline confirmed by a consecutive assessment at least 4 wk after first documentation. Stable Disease (irSD): not meeting criteria for irCR or irPR, in absence of irPD.

Secondary Outcome Measures

1. Number of Participants With Adverse Events as a Measure of Safety and Tolerability Using Common Terminology Criteria for Adverse Events (CTCAE) V4. [Every week while patient is receiving pembrolizumab, assessed for up to 52 weeks]

   Toxicity and tolerability of pembrolizumab in subjects with refractory GCTs. All grade 3 and higher adverse events are reported.

2. Disease Assessment for Overall Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Criteria [From the start of treatment D1 every 6 weeks for initial 18 weeks, assessed for up to 52 weeks]

   ORR of single agent pembrolizumab in subjects with refractory GCTs, determined by sum of complete responses and partial responses for at least 3 months using RECIST 1.1 criteria

3. Disease Assessment for Duration of Disease Response [From the start of treatment D1 every 6 weeks for initial 18 weeks, assessed for up to 52 weeks]

   Duration of disease response

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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.

• Age ≥ 18 years at the time of consent.

• ECOG Performance Status of 0 or 1 within 14 days prior to registration for protocol therapy.

• Subjects must have histological or serological proof of metastatic germ cell neoplasm (gonadal or extragonadal primary) with disease not amenable to cure with either surgery or chemotherapy. Subjects with seminoma and non-seminoma are eligible, as are women with ovarian GCTs.

• Subjects must have evidence of recurrent or metastatic carcinoma by one or more of the following: the appearance of metastatic disease on chest x-ray or CT scan, or the appearance of rising 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. Subjects with only evidence of disease as 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.

• Subjects must have received initial cisplatin based combination therapy, such as bleomycin-etoposide-cisplatin (BEP), cisplatin-etoposide (EP), etoposide-ifosfamide-cisplatin (VIP), or similar regimens AND demonstrated progression following the administration of at least one 'salvage' regimen for advanced germ cell neoplasm, such as high dose chemotherapy, paclitaxel-ifosfamide-cisplatin (TIP), or vinblastine-ifosfamide-cisplatin (VeIP).

• "Failure" of prior therapy is defined as: a >25% increase in the products of perpendicular diameters of measurable tumor masses during prior therapy which are not amenable to surgical resection; the presence of new tumors which are not amenable to surgical resection; 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: Subjects with clinically growing "teratoma" (normal declining tumor markers and radiographic or clinical progression) should be considered for surgery.

• Subjects are eligible after first line platinum based chemotherapy if their disease has relapsed and they have Primary Mediastinal Non Seminomatous Germ Cell tumor (PMNSGCT) or late relapse (> 2 years) not amenable to surgical resection.

• Subjects must be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g., inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the sponsor investigator

• Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication . Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.

• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

• Measurable disease according to RECIST v1.1 obtained by imaging within 28 days prior to registration.

Exclusion Criteria:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

• Has a known history of active TB (Bacillus Tuberculosis)

• Hypersensitivity to pembrolizumab or any of its excipients.

• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events (AE) due to agents administered more than 4 weeks earlier.

• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. NOTE 1: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. NOTE 2: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e,. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

• Presence of interstitial lung disease or history of pneumonitis requiring treatment with corticosteroids.

• Has an active infection requiring systemic therapy.

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

• Has received prior therapy with PD-1, PD-L1, or CTLA-4 inhibitors.

• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

• Has received a live vaccine within 30 days of planned start of study therapy. NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
2	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Nasser Hanna, M.D.
• Hoosier Cancer Research Network
• Merck Sharp & Dohme LLC

Investigators

• Study Chair: Nasser Hanna, M.D., Hoosier Cancer Research Network

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Hoosier Cancer Research Network Website

Publications

None provided.

• Responsible Party: Nasser Hanna, M.D., Sponsor-Investigator, Hoosier Cancer Research Network
• ClinicalTrials.gov Identifier: NCT02499952
• Other Study ID Numbers: HCRN GU14-206
• First Posted: Jul 16, 2015
• Last Update Posted: Jul 11, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Nasser Hanna, M.D., Sponsor-Investigator, Hoosier Cancer Research Network: Pembrolizumab; MK-3475; PMNSGCT; PD-L1; Non Seminomatous Germ Cell Tumors
• Additional relevant MeSH terms: Neoplasms; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Testicular Neoplasms; Genital Neoplasms, Male; Genital Neoplasms, Female; Mediastinal Neoplasms; Pembrolizumab

Study Results

Participant Flow

Arm/Group Title	Experimental Arm
Arm/Group Description	Pembrolizumab Pembrolizumab: 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or after 52 weeks of therapy.
Period Title: Overall Study
STARTED	12
COMPLETED	2
NOT COMPLETED	10

Baseline Characteristics

Arm/Group Title	Experimental Arm
Arm/Group Description	Pembrolizumab Pembrolizumab: 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or after 52 weeks of therapy.
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 100%
>=65 years	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	38
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	12 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	12 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 8.3%
White	11 91.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%
Location Of Primary Tumor (Count of Participants)
Testis	11 91.7%
Retroperitoneum	0 0%
Mediastinum	1 8.3%
Tumor Histology (Count of Participants)
Seminoma	0 0%
Nonseminoma	12 100%
Predominant Histology (Count of Participants)
Choriocarcinoma	3 25%
Embryonal carcinoma	5 41.7%
Teratoma	1 8.3%
Yolk sac tumor	3 25%
Number of Previous Chemotherapy Regimens (Count of Participants)
1	1 8.3%
2	0 0%
3	7 58.3%
4	2 16.7%
5	1 8.3%
6	1 8.3%
ECOG Performance Status (Count of Participants)
ECOG 0	5 41.7%
ECOG 1	7 58.3%
Metastatic Site(s) (participants) [Number]
Retroperitoneum	5 41.7%
Pulmonary	9 75%
Non Pulmonary Visceral Metastasis	5 41.7%

Outcome Measures

1. Primary Outcome

Title	Clinical Benefit Rate (CBR)
Description	CBR of single agent pembrolizumab in subjects with refractory germ cell tumors (GCTs), determined by sum of complete responses, partial responses, and stable disease for at least 3 months using Immune Related Response Criteria (irRC). Complete Response(irPR): Disappearance of all lesions in two consecutive observations not less than 4 wk apart. Partial Response (irPR): decrease in tumor burden ≥50 %relative to baseline confirmed by a consecutive assessment at least 4 wk after first documentation. Stable Disease (irSD): not meeting criteria for irCR or irPR, in absence of irPD.
Time Frame	up to 18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Arm
Arm/Group Description	Pembrolizumab Pembrolizumab: 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or after 52 weeks of therapy.
Measure Participants	12
Number [percentage of participants w/ clinical b]	0 0%

2. Secondary Outcome

Title	Number of Participants With Adverse Events as a Measure of Safety and Tolerability Using Common Terminology Criteria for Adverse Events (CTCAE) V4.
Description	Toxicity and tolerability of pembrolizumab in subjects with refractory GCTs. All grade 3 and higher adverse events are reported.
Time Frame	Every week while patient is receiving pembrolizumab, assessed for up to 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Arm
Arm/Group Description	Pembrolizumab Pembrolizumab: 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or after 52 weeks of therapy.
Measure Participants	12
Skin and subcutaneous tissue disorders	1 8.3%
Noncardiac chest pain	1 8.3%
Anemia	1 8.3%
Sciatic pain	1 8.3%

3. Secondary Outcome

Title	Disease Assessment for Overall Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Criteria
Description	ORR of single agent pembrolizumab in subjects with refractory GCTs, determined by sum of complete responses and partial responses for at least 3 months using RECIST 1.1 criteria
Time Frame	From the start of treatment D1 every 6 weeks for initial 18 weeks, assessed for up to 52 weeks

Outcome Measure Data

Analysis Population Description

Data for this secondary outcome measure was not collected or analyzed due to the early termination of this study.

Arm/Group Title	Experimental Arm
Arm/Group Description	Pembrolizumab Pembrolizumab: 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or after 52 weeks of therapy.
Measure Participants	0

4. Secondary Outcome

Title	Disease Assessment for Duration of Disease Response
Description	Duration of disease response
Time Frame	From the start of treatment D1 every 6 weeks for initial 18 weeks, assessed for up to 52 weeks

Outcome Measure Data

Analysis Population Description

Data for this secondary outcome measure was not collected or analyzed due to the early termination of this study.

Arm/Group Title	Experimental Arm
Arm/Group Description	Pembrolizumab Pembrolizumab: 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or after 52 weeks of therapy.
Measure Participants	0

Adverse Events

Time Frame	6 months.
Arm/Group Title	Experimental Arm
Arm/Group Description	Pembrolizumab Pembrolizumab: 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or after 52 weeks of therapy.
All Cause Mortality
	Experimental Arm
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Experimental Arm
	Affected / at Risk (%)	# Events
Total	2/12 (16.7%)
Blood and lymphatic system disorders
ANEMIA	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
BACK PAIN	1/12 (8.3%)	1
Other (Not Including Serious) Adverse Events
	Experimental Arm
	Affected / at Risk (%)	# Events
Total	11/12 (91.7%)
Blood and lymphatic system disorders
BLOOD AND LYMPHATIC SYSTEM DISORDERS	1/12 (8.3%)	1
Cardiac disorders
ATRIAL FIBRILLATION	1/12 (8.3%)	1
Ear and labyrinth disorders
TINNITUS	1/12 (8.3%)	1
Endocrine disorders
HYPOTHYROIDISM	1/12 (8.3%)	1
Eye disorders
BLURRED VISION	1/12 (8.3%)	1
PHOTOPHOBIA	1/12 (8.3%)	1
Gastrointestinal disorders
ABDOMINAL PAIN	3/12 (25%)	4
CONSTIPATION	2/12 (16.7%)	3
DIARRHEA	3/12 (25%)	3
DYSPHAGIA	1/12 (8.3%)	1
NAUSEA	5/12 (41.7%)	5
VOMITING	4/12 (33.3%)	6
General disorders
EDEMA LIMBS	2/12 (16.7%)	2
FATIGUE	6/12 (50%)	8
FLU LIKE SYMPTOMS	2/12 (16.7%)	2
NON-CARDIAC CHEST PAIN	2/12 (16.7%)	3
Metabolism and nutrition disorders
ANOREXIA	1/12 (8.3%)	1
HYPERCALCEMIA	1/12 (8.3%)	1
HYPERGLYCEMIA	1/12 (8.3%)	2
HYPOPHOSPHATEMIA	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
BACK PAIN	1/12 (8.3%)	1
CHEST WALL PAIN	1/12 (8.3%)	1
FLANK PAIN	2/12 (16.7%)	2
GENERALIZED MUSCLE WEAKNESS	1/12 (8.3%)	1
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER	2/12 (16.7%)	3
PAIN IN EXTREMITY	1/12 (8.3%)	1
Nervous system disorders
HEADACHE	1/12 (8.3%)	1
NERVOUS SYSTEM DISORDERS	1/12 (8.3%)	2
Psychiatric disorders
ANXIETY	1/12 (8.3%)	1
Renal and urinary disorders
ACUTE KIDNEY INJURY	1/12 (8.3%)	1
Reproductive system and breast disorders
PELVIC PAIN	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
COUGH	2/12 (16.7%)	2
DYSPNEA	2/12 (16.7%)	2
LARYNGEAL HEMORRHAGE	1/12 (8.3%)	1
SORE THROAT	1/12 (8.3%)	1
Skin and subcutaneous tissue disorders
DRY SKIN	2/12 (16.7%)	2
HYPERHIDROSIS	1/12 (8.3%)	1
PRURITUS	1/12 (8.3%)	1
RASH MACULO-PAPULAR	1/12 (8.3%)	1
SKIN AND SUBCUTANEOUS TISSUE DISORDERS	3/12 (25%)	4
SKIN ATROPHY	1/12 (8.3%)	2

Limitations/Caveats

This study was terminated early due to not meeting the primary efficacy endpoint at a pre-planned interim analysis.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.