A Phase I Study of Zalypsis (PM00104) in Subjects With Advanced Malignant Solid Tumors or Lymphoma

• Sponsor: PharmaMar (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00359294
• Collaborator: (none)
• Enrollment: 12
• Locations: 2
• Arm: 1
• Duration (Months): 28.1
• Patients Per Site: 6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Phase I trial, dose escalating, prospective, open-label, non-randomized, multicenter study. The purpose is to determine the safety, tolerability, dose limiting toxicity (DLT) and recommended dose (RD) of PM00104, administered intravenously over 1 hour daily for 5 days every 3 weeks (this is considered as 1 cycle) to subjects with advanced malignant solid tumors or lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors; Lymphoma	Drug: PM00104	Phase 1

Detailed Description

Phase I trial, dose escalating, prospective, open-label, non-randomized, multicenter study. The purpose is to determine the safety, tolerability, dose limiting toxicity (DLT) and recommended dose (RD) of PM00104, administered intravenously over 1 hour daily for 5 days every 3 weeks (this is considered as 1 cycle) to subjects with advanced malignant solid tumors or lymphoma. Secondary objectives are to determine the preliminary pharmacokinetics of PM00104, to evaluate the relationship between pharmacokinetics/pharmacodynamics and to evaluate the preliminary antitumor activity of PM00104. Dose-escalation guidelines will follow an accelerated phase I design for conventional cytotoxic agents in order to minimize the number of subjects treated at the subtoxic dose levels. The trial will be conducted in compliance with the protocol, Good clinical practice (GCP) and applicable regulatory requirements.

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 I Multicenter, Open-label, Dose-escalating Clinical and Pharmacokinetic Study of PM00104 Administered Intravenously Over 1 Hour Daily for 5 Days, Every 3 Weeks, to Subjects With Advanced Malignant Solid Tumors or Lymphoma.
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Sep 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zalypsis (PM00104)	Drug: PM00104; Intravenously over 1 hour daily for 5 days, every 3 weeks.; Other Names: Zalypsis

Outcome Measures

Primary Outcome Measures

1. Patients With Dose Limiting Toxicities (DLT) [During the first cycle (21 days)]

   DLTs were defined as follows: Hematological adverse events: Any grade 4 neutropenia (absolute neutrophil count (ANC) < 0.5 x109/l) for longer than five days; Any grade 4 neutropenia accompanied by fever (at least 38.5°C); Any grade 4 neutropenia and sepsis or other severe infection; Any grade 4 thrombocytopenia. Any other grade 3/4 non-hematological adverse event (AE) and any increase of cardiac troponin I ≥0.1 ng/ml together with evidence of cardiac damage by electrocardiogram (ECG) or echocardiogram (ECHO), except for untreated nausea/vomiting or hypersensitivity reactions. Decrease in left ventricular ejection fraction (LVEF) > 20% compared to the patient's baseline value and/or LVEF < 50% below normal limits for the institution. Delay in the initiation of a subsequent dose exceeding two weeks due to drug related AEs

Secondary Outcome Measures

1. Overall Best Tumor Response [every six weeks while on study, up to 2 years]

   Best tumor response was defined as the best response achieved during the study according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete response (CR): disappearance of all lesions; Partial response (PR): ≥10% decrease in target lesion size or ≥15% decrease in tumor density; Disease progression (PD): ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; Stable disease (SD): none of the CR, PR, or PD criteria met; RECIST,

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Voluntary written informed consent of the subject obtained before any study-specific procedure.

2. Histologically or cytologically confirmed malignant solid tumor or lymphoma.

3. Subjects with malignancies that are not otherwise curable or for which no effective standard therapy exists.

4. Age ≥ 18 years.

5. Subject with measurable or non-measurable disease using the RECIST criteria

6. Recovery from any drug-related adverse event related to previous treatment, excluding alopecia and NCI-CTCAE grade < 2 peripheral neuropathy.

7. Laboratory values within 7 days prior to first infusion:

• Platelet count ≥ 100 x109/L, hemoglobin ≥ 9 g/dL and absolute neutrophil count (ANC) ≥ 1.5 x109/L.

• Alkaline phosphatase ≤ 2.5 x the upper limit of normal (ULN) (≤ 5 x ULN in case of extensive bone metastases)

• Aspartate aminotransferase (AST): ≤ 2.5 x ULN

• Alanine aminotransferase (ALT): ≤ 2.5 x ULN

• Total bilirubin: ≤ 1.5 ULN, unless due to Gilbert's syndrome.

• Creatinine: ≤ ULN, or calculated creatinine clearance: ≥ 60 mL/min (calculated from the Cockcroft-Gault formula; see Appendix III).

• Albumin: ≥ 2.5 g/dL.

• Partial thromboplastin within normal limits for the institution

• International normalized ratio (INR) within normal limits for the institution (unless due to oral anticoagulation)

1. Performance status (ECOG) ≤ 1

2. Life expectancy ≥ 3 months.

3. Left ventricular ejection fraction (LVEF) within normal limits for the institution (LVEF of at least 50%).

4. Women of childbearing potential must have a negative serum pregnancy test before study entry. Both men and women must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months after discontinuation of treatment. Acceptable methods of contraception include complete abstinence, Intrauterine device, oral contraceptive, subdermal implant and double barrier (condom with a contraceptive sponge or contraceptive suppository).

Exclusion Criteria:

1. Prior therapy with PM00104

2. Pregnant or lactating women.

3. Less than 4 weeks from radiation therapy (8 weeks in case of extensive prior radiotherapy) or last dose of hormonal therapy, biological therapy or chemotherapy (6 weeks in case of nitrosourea, mitomycin C).

4. Prior high dose chemotherapy that needed bone marrow transplant support.

5. Subjects with untreated or uncontrolled brain or meningeal metastases.

6. Other relevant diseases or adverse clinical conditions:

• Increased cardiac risk as defined by:

• History or presence of unstable angina.

• History or presence of myocardial infarction.

• Congestive heart failure.

• Symptomatic arrhythmia or any arrhythmia requiring ongoing treatment.

• Abnormal ECG (i.e., patients with the following are excluded: QT prolongation-corrected QT interval > 480 msec-, signs of cardiac enlargement or hypertrophy, bundle branch block, partial bundle branch blocks, signs of ischemia or necrosis, Wolff-Parkinson-White patterns).

• History or presence of valvular heart disease.

• Uncontrolled arterial hypertension despite optimal medical therapy.

• Previous mediastinal radiotherapy.

• Previous treatment with doxorubicin at cumulative doses in excess of 400 mg/m2

• History of significant neurological or psychiatric disorders.

• Active infection.

• Significant non-neoplastic liver disease (e.g., cirrhosis, chronic active hepatitis).

• Significant non-neoplastic renal disease.

• Immunocompromised subjects, including subjects known to be infected by human immunodeficiency virus (HIV).

• Uncontrolled endocrine diseases (e.g., diabetes mellitus, hypothyroidism or hyperthyroidism, adrenal disorder) requiring relevant changes in medication within the last month or hospital admission within the last 3 months.

• Any other major illness that, in the investigator's judgment, could substantially increase the risk associated with the subject's participation in this study.

1. Limitation of the subject's ability to comply with the treatment or to follow-up at a participating center. Subjects registered on this trial must be treated and followed at a participating center.

2. Treatment with any investigational product in the 30 days period prior to the first infusion.

3. Known hypersensitivity to any of the components of the drug product, including sucrose or potassium phosphate.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02115
2	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111-2497

Sponsors and Collaborators

• PharmaMar

Investigators

• Principal Investigator: Roger Bryan Cohen, MD, Fox Chase Cancer Center
• Principal Investigator: Eunice Lee Kwak, MD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Sponsor's website

Publications

None provided.

• Responsible Party: PharmaMar
• ClinicalTrials.gov Identifier: NCT00359294
• Other Study ID Numbers: PM104-A-002-05
• First Posted: Aug 2, 2006
• Last Update Posted: Jul 28, 2021
• Last Verified: Jul 1, 2021

• Keywords provided by PharmaMar: Tumor; Lymphoma; Zalypsis; PharmaMar; PM00104
• Additional relevant MeSH terms: Lymphoma

Study Results

Participant Flow

Recruitment Details	Twelve patients were enrolled and 11 patients were treated between 9 May 2006 (first consent signed) and 10 September 2008 (last follow-up). The first dose of the first cycle was administered on 15 May 2006 and the last dose of the last cycle was administered on 20 June 2008

Arm/Group Title	Dose Level I	Dose-level II	Dose-level III	Dose Level IV	Dose Level V
Arm/Group Description	PM0104: 0.053 mg/m2	PM00104: 0.106 mg/m2	PM00104: 0.212 mg/m2	PM00104: 0.318 mg/m2	PM0104: 0.475 mg/m2
Period Title: Overall Study
STARTED	1	1	3	4	3
COMPLETED	0	0	0	0	0
NOT COMPLETED	1	1	3	4	3

Baseline Characteristics

Arm/Group Title	Dose-level I	Dose-level II	Dose-level III	Dose-level IV	Dose-level V	Total
Arm/Group Description	PM00104: 0.053 mg/m2	PM00104: 0.106 mg/m2	PM00104: 0.212 mg/m2	PM00104: 0.318 mg/m2	PM00104: 0.475 mg/m2	Total of all reporting groups
Overall Participants	1	1	3	3	3	11
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	46	56	54	66.0	57	56
Sex: Female, Male (Count of Participants)
Female	1 100%	0 0%	1 33.3%	3 100%	2 66.7%	7 63.6%
Male	0 0%	1 100%	2 66.7%	0 0%	1 33.3%	4 36.4%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	1 100%	1 100%	3 100%	3 100%	2 66.7%	10 90.9%
Asian	0 0%	0 0%	0 0%	0 0%	1 33.3%	1 9.1%
ECOG PS (participants) [Number]
PS 0	0 0%	0 0%	0 0%	1 33.3%	2 66.7%	3 27.3%
PS 1	1 100%	1 100%	3 100%	2 66.7%	1 33.3%	8 72.7%
Primary tumor (Count of Participants)
Soft tissue sarcoma	0 0%	1 100%	0 0%	1 33.3%	2 66.7%	4 36.4%
Cervix adenocarcinoma	0 0%	0 0%	1 33.3%	1 33.3%	0 0%	2 18.2%
Colorectal adenocarcinoma	1 100%	0 0%	0 0%	1 33.3%	0 0%	2 18.2%
Head and neck carcinoma	0 0%	0 0%	1 33.3%	0 0%	0 0%	1 9.1%
Pseudomyxoma peritoneii	0 0%	0 0%	1 33.3%	0 0%	0 0%	1 9.1%
Unknown origin	0 0%	0 0%	0 0%	0 0%	1 33.3%	1 9.1%
Prior chemotherapy (Count of Participants)
2-5 lines	1 100%	1 100%	1 33.3%	2 66.7%	2 66.7%	7 63.6%
≥ 6 lines	0 0%	0 0%	2 66.7%	1 33.3%	1 33.3%	4 36.4%
Prior Surgery (Count of Participants)
Count of Participants [Participants]	1 100%	0 0%	3 100%	3 100%	3 100%	10 90.9%
Prior radiotherapy (Count of Participants)
Count of Participants [Participants]	1 100%	0 0%	2 66.7%	2 66.7%	1 33.3%	6 54.5%

Outcome Measures

1. Primary Outcome

Title	Patients With Dose Limiting Toxicities (DLT)
Description	DLTs were defined as follows: Hematological adverse events: Any grade 4 neutropenia (absolute neutrophil count (ANC) < 0.5 x109/l) for longer than five days; Any grade 4 neutropenia accompanied by fever (at least 38.5°C); Any grade 4 neutropenia and sepsis or other severe infection; Any grade 4 thrombocytopenia. Any other grade 3/4 non-hematological adverse event (AE) and any increase of cardiac troponin I ≥0.1 ng/ml together with evidence of cardiac damage by electrocardiogram (ECG) or echocardiogram (ECHO), except for untreated nausea/vomiting or hypersensitivity reactions. Decrease in left ventricular ejection fraction (LVEF) > 20% compared to the patient's baseline value and/or LVEF < 50% below normal limits for the institution. Delay in the initiation of a subsequent dose exceeding two weeks due to drug related AEs
Time Frame	During the first cycle (21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose-level I	Dose-level II	Dose-level III	Dose-level IV	Dose-level V
Arm/Group Description	PM00104: 0.053 mg/m2	PM00104: 0.106 mg/m2	PM00104: 0.212 mg/m2	PM00104: 0.318 mg/m2	PM00104: 0.475 mg/m2
Measure Participants	1	1	3	3	3
Number [participants]	0 0%	0 0%	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Overall Best Tumor Response
Description	Best tumor response was defined as the best response achieved during the study according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete response (CR): disappearance of all lesions; Partial response (PR): ≥10% decrease in target lesion size or ≥15% decrease in tumor density; Disease progression (PD): ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; Stable disease (SD): none of the CR, PR, or PD criteria met; RECIST,
Time Frame	every six weeks while on study, up to 2 years

Outcome Measure Data

Analysis Population Description

11 patients were evaluable for antitumor activity

Arm/Group Title	Dose-level I	Dose-level II	Dose-level III	Dose-level IV	Dose-level V
Arm/Group Description	PM00104: 0.053 mg/m2	PM00104: 0.106 mg/m2	PM00104: 0.212 mg/m2	PM00104: 0.318 mg/m2	PM00104: 0.475 mg/m2
Measure Participants	1	1	3	3	3
SD	0 0%	0 0%	3 100%	2 66.7%	1 33.3%
PD	1 100%	1 100%	0 0%	1 33.3%	2 66.7%

Adverse Events

Time Frame	From first infusion to study termination, up to 2 years
Adverse Event Reporting Description	All patients treated with PM00104 were evaluable for safety
Arm/Group Title	PM00104
Arm/Group Description	All patients were to receive treatment for at least one 3-week cycle, which consisted of PM00104 administrations daily for 5 days and all study evaluations up to the next treatment cycle. Cycles were to be repeated every three weeks until disease progression, unacceptable toxicity, intercurrent serious illness, withdrawal of informed consent by the patient, Investigator's opinion, or treatment delay > 2 weeks. Patients were considered to be on study for the duration of their treatment and for the first 30 days following treatment discontinuation, defined as the day of the last PM00104 administration
All Cause Mortality
	PM00104
	Affected / at Risk (%)	# Events
Total	0/11 (0%)
Serious Adverse Events
	PM00104
	Affected / at Risk (%)	# Events
Total	5/11 (45.5%)
Gastrointestinal disorders
Nausea	1/11 (9.1%)	1
Pancreatitis NOS	1/11 (9.1%)	1
Injury, poisoning and procedural complications
Pyrexia (Febrile Nonhaemolytic transfusion reaction)	1/11 (9.1%)	1
Radiation pneumonitis	1/11 (9.1%)	1
Metabolism and nutrition disorders
Dehydration	1/11 (9.1%)	1
Failure to thrive	1/11 (9.1%)	1
Musculoskeletal and connective tissue disorders
Pain in limb	1/11 (9.1%)	1
Other (Not Including Serious) Adverse Events
	PM00104
	Affected / at Risk (%)	# Events
Total	11/11 (100%)
Blood and lymphatic system disorders
Anaemia NOS	3/11 (27.3%)	5
Lymphadenopathy	1/11 (9.1%)	2
Cardiac disorders
Atrial fibrillation	1/11 (9.1%)	1
Palpitations	1/11 (9.1%)	2
Supraventricular arrhythmia NOS	1/11 (9.1%)	2
Tachycardia NOS	1/11 (9.1%)	1
Eye disorders
Dry eye NOS	1/11 (9.1%)	1
Eyelid ptosis	1/11 (9.1%)	1
Visual disturbance NOS	1/11 (9.1%)	1
Vitreous detachment	1/11 (9.1%)	2
Gastrointestinal disorders
Abdominal discomfort	2/11 (18.2%)	2
Abdominal distension	1/11 (9.1%)	1
Abdominal pain NOS	2/11 (18.2%)	2
Constipation	4/11 (36.4%)	8
Diarrhoea NOS	4/11 (36.4%)	7
Dyspepsia	1/11 (9.1%)	1
Flatulence	2/11 (18.2%)	2
Nausea	8/11 (72.7%)	19
Retching	1/11 (9.1%)	1
Stomatitis	3/11 (27.3%)	3
Tongue oedema	1/11 (9.1%)	1
Toothache	1/11 (9.1%)	1
Vomiting NOS	5/11 (45.5%)	11
General disorders
Chest pressure sensation	1/11 (9.1%)	1
Fatigue	6/11 (54.5%)	23
Influenza like illness	1/11 (9.1%)	2
Injection site pain	1/11 (9.1%)	2
Injection site reaction NOS	6/11 (54.5%)	14
Injection site vesicles	1/11 (9.1%)	2
Pyrexia	4/11 (36.4%)	6
Tenderness NOS	1/11 (9.1%)	2
Weakness	1/11 (9.1%)	2
Immune system disorders
Hypersensitivity NOS	1/11 (9.1%)	2
Seasonal allergy	1/11 (9.1%)	1
Infections and infestations
Groin infection	1/11 (9.1%)	1
Herpes zoster	1/11 (9.1%)	1
Infection NOS	2/11 (18.2%)	3
Nasopharyngitis	1/11 (9.1%)	2
Upper respiratory tract infection NOS	1/11 (9.1%)	1
Urinary tract infection NOS	2/11 (18.2%)	2
Investigations
Weight decreased	3/11 (27.3%)	4
Metabolism and nutrition disorders
Anorexia	7/11 (63.6%)	16
Dehydration	3/11 (27.3%)	6
Hypercalcaemia	1/11 (9.1%)	3
Hypoglycaemia NOS	1/11 (9.1%)	2
Hypomagnesaemia	2/11 (18.2%)	11
Musculoskeletal and connective tissue disorders
Back pain	3/11 (27.3%)	5
Muscle weakness NOS	1/11 (9.1%)	1
Myalgia	2/11 (18.2%)	5
Tumour pain	2/11 (18.2%)	2
Arthralgia	1/11 (9.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever	1/11 (9.1%)	1
Nervous system disorders
Dizziness	1/11 (9.1%)	1
Headache NOS	2/11 (18.2%)	2
Paraesthesia	3/11 (27.3%)	6
Visual field defect NOS	1/11 (9.1%)	1
Psychiatric disorders
Anxiety	1/11 (9.1%)	1
Confusional state	1/11 (9.1%)	1
Depression	2/11 (18.2%)	3
Insomnia	2/11 (18.2%)	2
Renal and urinary disorders
Difficulty in micturition	1/11 (9.1%)	1
Dysuria	1/11 (9.1%)	1
Haematuria	1/11 (9.1%)	1
Urethral obstruction	1/11 (9.1%)	1
Urinary frequency	1/11 (9.1%)	3
Urine odour abnormal	1/11 (9.1%)	1
Reproductive system and breast disorders
Breast mass NOS	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders
Cough	3/11 (27.3%)	8
Dyspnoea NOS	3/11 (27.3%)	4
Pharyngitis	1/11 (9.1%)	1
Pleuritic pain	1/11 (9.1%)	2
Rhinitis NOS	1/11 (9.1%)	1
Rhinorrhoea	1/11 (9.1%)	1
Wheezing	1/11 (9.1%)	1
Skin and subcutaneous tissue disorders
Contusion	1/11 (9.1%)	1
Night sweats	1/11 (9.1%)	2
Pruritus NOS	1/11 (9.1%)	1
Rash NOS	2/11 (18.2%)	2
Skin disorder NOS	1/11 (9.1%)	1
Subcutaneous nodule	1/11 (9.1%)	1
Sweating increased	2/11 (18.2%)	3
Urticaria NOS	1/11 (9.1%)	1
Vascular disorders
Haematoma NOS	1/11 (9.1%)	2
Hypotension NOS	2/11 (18.2%)	2
Lymphoedema NOS	1/11 (9.1%)	1
Phlebitis NOS	1/11 (9.1%)	1
Thrombosis	1/11 (9.1%)	2

Limitations/Caveats

This phase I study was prematurely closed due to a low recruiting rate as well as to the perception that this could be an unpractical dosing schedule when compared to other schedules evaluated in the clinical development program of PM00104.

More Information

Certain Agreements

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